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PubMed1983

Experimental study of the effect of diethylstilbestrol on the development of the human female reproductive tract.

Female genital tracts from human embryos and fetuses 5-17 weeks post fertilization were grown for 1-3 months in vivo as grafts to athymic female nude mice. The nude mice were either untreated or treated with diethylstilbestrol (DES). In control (untreated) hosts, anticipated normal development occurred with a high degree of precision. Müllerian ducts fused and proliferated, forming a solid uterovaginal canal that later canalized and formed a normal vaginal mucosa. Uterine glands appeared, and the uterine tube developed its highly plicated mucosa. Under the influence of DES, many of these normal developmental processes were adversely affected. Müllerian epithelium was largely obliterated in the fallopian tube and uterine corpus, mesenchymal stratification into endometrial stroma and myometrium was suppressed, plical development in the fallopian tube was inhibited, cervicovaginal epithelial development was abnormal, and vaginal adenosis was observed in several specimens. This in vivo model of human development is discussed in terms of its potential for resolving the mechanisms of normal human genital development and understanding the teratogenic action of DES on the developing human genital tract.

Animals↗

PubMed1983

Suppression of diethylstilbestrol and N-nitrosobutylurea-induced mammary and pituitary tumorigenesis in rats by prolonged treatment with 2-bromoergocryptine.

Inbred male W/Fu rats were castrated at 40 days of age (24) and divided into five groups. Group I was given no further treatment. Groups II, IV, and V received pellet implants of 5.0 mg diethylstilbestrol (DES) concurrently with the castration. At 50 to 55 days of age, Groups II, IV, and V were given drinking water containing 5.0 mg N-nitrosobutylurea (NBU)/day for 30 days. This amount does not induce mammary tumors (MTs) in castrated male rats (24) or in female rats (31). At the termination of NBU treatment, Group V received further daily s.c. injections of 2-bromoergocryptine (CB-154; 0.4 mg/100 g body weight) four times/week throughout the experiment. None of the castrated rats or rats castrated and treated with NBU alone developed MT or pituitary tumors (PTs). Incidences of MT and PT in Groups III, IV, and V were three of nine (33%) and seven of nine (78%), 15 of 17 (88%) and 12 of 17 (17%), and three of 20 (15%) and four of 20 (20%), respectively. The treatment with DES alone resulted in the concurrent development of MT and PT in castrated male rats (Group III), and further NBU treatment markedly accelerated the development and growth of MT (Group IV). CB-154 treatment profoundly reduced the incidences of both MT and PT in castrated male rats given DES and NBU (Group V). This treatment also depressed the increase in the number of MT per rat with MT, the pituitary and epididymis weights, and the serum prolactin levels caused by DES treatment. These results indicate that prolonged treatment with CB-154 was effective in the suppression of the concurrent tumorigenesis of mammary and pituitary glands, and the elevation of circulating prolactin levels, by counteracting the continuous stimulatory action of DES. In addition, CB-154 was able to reverse DES-enhanced growth of the epididymis in castrated male rats, suggesting a direct action of prolactin.

Animals↗

PubMed1981

Osseous changes and osteosacomas in mice continuously fed diets containing diethylstilbestrol or 17 beta-estradiol.

In a study on the long-term effects of dietary diethylstilbestrol or 17 beta-estradiol on C3H mice, estrogens induced a proliferation of osseous trabeculae and increased the incidence and hastened the development of osteofibrotic areas in the sterna. There were 6 osteosarcomas, 2 having metastases, in 1,242 mice fed dietary estrogens over 360 days, but none in 356 untreated controls. These tumors were reviewed along with 4 early sternal osteosarcomas selected from 17 osteosarcomas (only 1 in a control) found thus in two other ongoing comparable studies. In at least 1 case, and possibly in 2 other early cases, tumors were associated with areas of osteofibrosis, and 1 tumor was probably associated with proliferation of bony trabeculae in the medullary cavity.

Animals↗

PubMed1982

Induction of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol.

Mammary tumorigenesis was studied in female ACi rats after treatment with X-irradiation or neutron-irradiation, with or without diethylstilbestrol (DES) treatment. The mortality-corrected cumulative tumor rate based on all mammary neoplasms and the mortality-corrected incidence based on the first neoplasms only have been derived. In non-DES-treated animals, at the relatively high radiation doses studied, all dose-effect relationships were consistent with relative biological effectiveness (RBE) values slightly in excess of 10. In DES-treated rats definite findings were observed at neutron doses as low as 0.01 Gy (1 rad). The dose-effect relationship in DES-treated rats showed a strong sublinearly (dose exponent less than 1) at low neutron doses. RBE values in DES-treated rats increased in inverse proportion to the square root of the neutron dose, and exceeded 100 at a neutron dose of 0.01 Gy (1 rad).

Adenocarcinoma↗

PubMed1981

Urinary monitoring for diethylstilbestrol in male chemical workers.

Between 1969 and 1972 diethylstilbestrol (DES) accounted for 25 instances of breast tenderness and enlargement in male chemical workers in a DES production area of a large chemical plant. A gas chromatographic analysis for urinary DES was performed at three spaced intervals over a 90-day work span. All full-time workers who wore air suits when necessary developed increasing levels of DES upon increasing days of exposure. At a certain range of excretion (40 micrograms/ml/24 hours) two workers became symptomatic. DES was also detected in one helper and in two individuals not directly connected with the area of known exposure. Although no federal standard for DES exists, the following evidence points to the actuality of hazardous levels of exposure: (1) there had been a persistent history of DES reactions year after year; (2) high urine levels and adverse reactions were found in workers participating in the medical studies of this evaluation; and (3) there was widespread DES contamination of buildings and equipment, extending as far away as the lunchroom in a separate building.

Adult↗

PubMed1981

Diethylstilbestrol and other sex hormones during pregnancy.

Intrauterine exposure to diethylstilbestrol (DES) has been associated with ths subsequent rare development of clear cell adenocarcinoma of the vagina and cervix in exposed female progeny. These tumors have been seen thus far in patients between the ages of 7 and 29 years. In addition, nonmalignant epithelial and structural genital alterations have been frequently observed. The epithelial changes of adenosis, ectropion, metaplasia, and potential neoplasia are considered. Thus far, no increased risk of squamous cell neoplasia has been demonstrated in DES-exposed subjects. However, increased pregnancy wastage, including premature birth, does appear to be more common among DES-exposed women; this increase may be related to the structural uterine and cervical changes that have occurred. DES-exposed men have been demonstrated to have anatomic genital changes, but the effects of these changes, if any, on male infertility are not known. Masculinization of the female external genitalia, including phallic enlargement and labioscrotal fusion, has been reported following intrauterine exposure to certain progestational agents and androgens.

Abnormalities, Drug-Induced↗

PubMed1982

Diethylstilbestrol: placental transfer, metabolism, covalent binding and fetal distribution in the Wistar rat.

The disposition of [14C]diethylstilbestrol (DES) was investigated in the near-term pregnant Wistar rat. Both constant maternal i.v. infusions and direct fetal i.p. injections of [14C]DES were utilized as exposure routes. Maternal femoral vein infusions (total dose: 0.3-0.4 mg of DES/kg of maternal b.wt.) resulted in a stable maternal plasma level of DES during a 3-hr period. At 3 hr, fetal plasma levels were 2 to 3 times higher than maternal plasma DES. The chorioallantoic placenta and visceral yolk sac concentrated DES to levels 5 to 7 times that in the maternal plasma. DES was highly concentrated in the extraembryonic membranes and did maintain high fetal plasma levels of DES. Fetal reproductive tract had total 14C-activity levels 20 to 25 times higher than those in maternal plasma. The extractable 14C-activity in the reproductive tract was 20% DES, 15% glucuronides and 65% oxidative metabolites (beta-dienestrol, 4-OH-propiophenone, omega-OH-DES + unknowns). Fetal liver contained DES (approximately 2%), glucuronides (75%) and oxidative metabolites (approximately 20%). 14C analysis of the whole fetus indicated that the DES was 75% and glucuronides was 25%. Maternal and fetal liver had similar metabolites. Direct fetal injections of [14C]DES resulted in similar metabolite profiles in fetal tissues. The degree of covalent binding of [14C]DES to cellular constituents was tissue-specific, especially the fetal reproductive tract. Thus, DES and its oxidative metabolites were concentrated in the fetus and selected fetal tissues. It is proposed that both the estrogenic activity of DES and the potential reactivity of its metabolites may be responsible for the toxicity expressed in the fetus. Inasmuch as direct fetal injections of [14C]DES resulted in high tissue localization of both oxidative and conjugative metabolites within the fetus, it is suggested that fetal tissues may metabolize DES.

Animals↗

PubMed1982

Increased induction of sister chromatid exchange by diethylstilbestrol in lymphocytes from pregnant and premenopausal women.

Cultures of whole blood from pregnant women (4 to 6 months), premenopausal women, postmenopausal women, and normal men were grown in the presence of varying concentrations (1 x 10(-5) M, 2 x 10(-5) M, and 4 x 10(-5) M) of diethylstilbestrol (DES), a synthetic estrogen and known carcinogen, to see if it had sex-related cytogenetic effects. DES induced sister chromatid exchanges in lymphocytes from pregnant and premenopausal women but had only a small effect at the highest concentration (4 x 10(-5) M) in lymphocytes from men and postmenopausal women. At all concentrations, the average number of sister chromatid exchanges was higher in lymphocytes from pregnant women than in those from premenopausal women. In lymphocytes from both a man and a pregnant woman, DES strongly inhibited cell proliferation in vitro. When lymphocytes from a man and a pregnant woman were cocultured in the presence of DES, only the lymphocytes of the woman responded with an increase in sister chromatid exchanges. This indicated that there is no interaction between DES and a factor present in the blood but that DES acts directly on each cell.

Adult↗

PubMed1982

Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol.

The association of intrauterine exposure to diethylstilbestrol (DES) and the subsequent development of reproductive tract abnormalities in young women has been well documented. Although the incidence of vaginal adenocarcinoma was low in the exposed population, vaginal adenosis, a nonmalignant abnormality, was quite common. In order to study the pathogenesis of adenocarcinoma and to determine the frequency of adenosis following prenatal exposure to DES, timed pregnant CD-1 mice were treated s.c. with DES (dose range, 5 to 100 micrograms/kg/day) on Days 9 though 16 of gestation. This period corresponds to major organogenesis of the reproductive tract in the mouse. Female offspring were sacrificed between 1 and 18 months of age. In addition to nonmalignant abnormalities, some of which have been described in women exposed prenatally to DES, two cases of vaginal adenocarcinoma (2%) were observed in 91 prenatally DES-treated animals. No comparable epithelial lesions were seen in 158 control female mice. One other case of adenocarcinoma of the vagina was reported previously by this laboratory using the prenatally exposed animal model. In another series of mice treated prenatally with DES, 100 micrograms/kg/day, 3 of 20 (15%) 1-month-old animals and one of 10 (10%) 18-month-old treated offspring had glandular epithelium abnormally located in the vaginal fornices (adenosis). Other cervicovaginal abnormalities observed after prenatal DES exposure included structural alterations, cervical enlargement, squamous metaplasia in the endocervical canal, excess keratinization of the ectocervix and vagina, transverse folds and basal cell hyperplasia in the upper vagina, and prominent Wolffian duct remnants. Thus, vaginal adenosis in the mouse does not appear to be a common abnormality following treatment with DES in utero. Neonatal exposure to DES on Days 1 to 5, on the other hand, resulted in six of eight (75%) animals with adenosis at 35 days of age. Since perinatal mouse studies have reported high incidences of vaginal adenosis, but, to our knowledge, no cases of vaginal adenocarcinoma, the results presented in this report suggest that the stage of cellular differentiation at the time of DES exposure may be critical in the final expression of these abnormalities.

Adenocarcinoma↗

PubMed1982

Pregnancy outcome in 98 women exposed to diethylstilbestrol in utero, their mothers, and unexposed siblings.

The reproductive capability and labor complications of 98 women exposed to diethylstilbestrol (DES) in utero were compared with those of 3 separate control groups. The controls consisted of 167 age-matched, normal women, 20 siblings not exposed to DES who had achieved pregnancy, and their mothers. Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. The controls also achieved a higher percentage of desired pregnancies overall; this was statistically significant (89.6 versus 75.0%, P less than .001). When compared with their mothers, however, the DES-exposed population achieved a greater percentage of desired, viable pregnancies (75.6 versus 67.0%, P less than .001). The unexposed siblings of the DES women achieved a higher percentage of desired, viable pregnancies than did their exposed sisters (86.9 versus 73.6%, P = .274), but less than the normal population (86.9 versus 89.6%).

Abortion, Incomplete↗

PubMedDate not supplied

[Chromosome aberrations and sister chromatid exchanges in a human lymphocyte culture exposed to diethylstilbestrol dipropionate].

Frequency of chromosome aberrations and sister chromatid exchanges (SCE) was studied in human lymphocyte culture treated with the synthetic nonsteroidal estrogen diethylstilbestrol-dipropionate in doses of 1.3 . 10(-7) M, 1.3 . 10(-6) M and 1.3 . 10(-5) M. Doses of 1.3 . 10(-6) M and 1.3 . 10(-5) M are shown to induce a significant increase in the chromosome aberration level mostly due to a rise in the number of polyploid cells. The same doses increase the frequency of SCE.

Adult↗

PubMed1982

Enhancing effect of diethylstilbestrol on urinary bladder carcinogenesis in neonatally castrated male rats.

The effects of diethylstilbestrol (DES) on the development of urinary bladder cancer induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in neonatally castrated rats and on metaplastic changes of the coagulating glands and ejaculatory ducts were studied. Pretreatment with DES during infancy increased the incidence of preneoplastic lesions, papillomas, and cancers of the urinary bladder in BBN-treated males. Pretreatment with DES was more effective in castrated males than in uncastrated males. BBN did not induce tumors of the coagulating glands or ejaculatory ducts, in which metaplastic changes were observed in DES-treated rats.

Animals↗

PubMed1982

Role of metabolic activation in the transplacental carcinogenicity of diethylstilbestrol.

Metabolic studies have shown a variety of oxidative pathways in the biotransformation of the synthetic estrogen, diethylstilbestrol (DES). The metabolic intermediates are reactive electrophiles and bind covalently to proteins and nucleic acids. DES and some of its metabolites have proven to be genotoxic in several assays using mammalian cells. Oxidative metabolism of DES has also been shown in rodent fetuses and even in the ultimate target organ of DES transplacental carcinogenicity, the fetal genital tract. These findings imply that reactive metabolites may play a role in DES fetotoxicity, and several mechanisms accounting for the organotropism of DES transplacental carcinogenicity are proposed.

Animals↗

PubMed1981

Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero: a clinical and pathologic study.

The anatomic, colposcopic, cytologic, and histologic findings of the cervix in 300 women exposed to diethylstilbestrol (DES) in utero are reported. Structural cervical abnormalities were found in 51.7% of these patients and an abnormal colposcopic examination was present in 50.6%. The initial interpretation of the pathologic specimens revealed that 26.6% of patients had cytologic or histologic evidence of cervical dysplasia. A uniform pathologic review demonstrated that 10.8% of the cytologic specimens and 37.5% of the histologic specimens had been overread by the initial pathologist. A correlation of the review cytology and histology revealed that the Papanicolaou smear sensitivity for the prediction of abnormal histology was 83.9% and specificity was 86.3%. The probability of an atypical cytologic finding predicting an abnormal histologic pattern was highly significant (P less than .00001). Colposcopic and structural cervical abnormalities were not predictive of an abnormal histologic diagnosis. Of the 18 patients (6%) with histologic evidence of mild-moderate dysplasia, 12 have been followed with no treatment, and cytologic and colposcopic examination has been normal. Marked dysplasia-carcinoma in situ was found in 14 patients (4.7%). Their therapy is summarized. These data strongly suggest that women exposed to DES may be followed safely with Papanicolaou smears and colposcopic examinations provided that both cytopathologists and colposcopists are cognizant of the metaplastic changes in the DES progeny that distinguish them from patients with cervical intraepithelial neoplasia (CIN) who were not exposed to DES. Biopsy should be performed only if indicated by cytologic atypia, colposcopic evidence of advanced CIN, or the presence of an invasive lesion.

Adolescent↗

PubMed1980

Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17 beta-estradiol.

To study the long term effects of estrogenic diets, 2160 virgin female C3H/Hel mice, having a high titer to the mammary tumor virus factor (MMTV), were fed diets containing 0, 10, 100, 500, or 1000 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 weeks of age; 1368 virgin female C3HeB/FeJ mice, having a low titer to the MMTV, were fed diets containing 0, 10, 1000, or 500 ppb DES from 6 to 136 weeks. In estrogen-treated mice, the incidence of cervical adenosis and of mammary hyperplastic alveolar nodules was increased and the time to development of mammary adenocarcinomas was shortened. These changes tended to increase with dose and time and appeared earlier in the C3H/HeJ mice. Other tumors observed included 32 cervical and 20 endometrial adenocarcinomas, 16 cervical granular cell myoblastomas, 12 peritoneal mesotheliomas involving the uterus, 2 cervical and 4 vaginal squamous cell carcinomas, 2 ovarian teratomas, 6 osteosarcomas, 25 pheochromocytomas and 3 thyroid carcinomas. Of these tumors, 1 cervical and 2 endometrial adenocarcinomas, and 4 pheochromocytomas occurred in C3HeB/FeJ control mice at 104-130 weeks; none occurred in C3H/HeJ controls. This study indicates that the MMTV facilitates the development of mammary lesions in C3H mice, that estrogens predispose C3H mice to endometrial and cervical adenocarcinomas, and that cervical adenosis may be a precursor of cervical adenocarcinoma in C3H mice and serve as an early indicator of the potential uterine carcinogenicity of a test compound. It supports the view that the C3H mouse may serve as an animal model for uterine adenocarcinomas and adenosis in women exposed to estrogens.

Animals↗

PubMedDate not supplied

Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol or 17beta--estradiol.

To study the long term effects of estrogen administration in mice, virgin female C3H/HeJ mice are being fed diets containing 0, 10, 100 or 500 ppb of diethylstilbestrol (DES) or 0, 100, 1000, or 5000 pph of 17beta-estradiol (E2) from 6 to 110 weeks of age. C3HeB/FeJ mice are being fed diets containing 08 10, 100, or 500 ppb DES FROM 6 TO 136 WEEKS OF AGE. Pathologic studies were conducted on 396 such mice sacrificed at 52 weeks and on over 500 others sacrificed at various intervals. After 52 weeks on 500 ppb DES or 5000 ppb E2, the cervix of both populations often showed stromal mucoid changes and adenosis characterized by focal replacement of squamous by columnar epithelium lining the cervical canal assoicated with glandular downgrowths into the subjacent stroma. The uterine horns showed hyperplastic glands, which often penetrated the muscularis, and focal endometrial and perivascular hyalin deposits. The ovaries showed atrophy with absence of corpora lutea. Ceroid deposits were increased in the ovaries and adrenals. Sternal bony trabeculae were increased. The incidence of uterine cervical adenosis and of mammary hyperplastic alveolar nodules and tumors (mainly type B, Dunn's classification), was higher in C3H/HeJ than in C3HeB/FeJ mice. Mice on lower doses of DES or E2 had less frequent and severe similar changes. Tumors observed to date only in estrogen-treated mice included 4 endometrial adenocarcinomas and an adenoacanthoma of a uterine horn, 14 cervical adenocarcinomas often appearing to arise from areas of adenosis, a vaginal squamous cell carcinoma, a cervical granular cell myoblastoma, 1 sternal and 3 cranial osteosarcomas, and a mesothelioma. The majority of the malignancies occurred in C3H/HeJ mice. These findings indicate that the mammary tumor virus factor facilitates DES-induced mammary tumorigenesis in C3H mice and may contribute to other DES-induced malignant and premalignant lesions.

Animals↗

PubMed1981

The effects of prenatal diethylstilbestrol exposure on the genitalia of pubertal Macaca mulatta. II. Male offspring.

In order evaluate the potential embryotoxic and fetotoxic effects of in utero diethylstilbestrol (DES) exposure on the developing offspring, 19 pregnant rhesus monkeys were administered 1 mg/day DES orally beginning on either day 19 (group I), 100 (group II) or 130 (group III) or gestation and termination on the day of natural birth or cesarean section. Five of ten male offspring are alive at 7 years of age. At 4 1/2 years of age, three of these five offspring exhibited one or more abnormalities of the external genitalia, including testicular hypoplasia, preputial adhesions and undescended testes. Semen analysis following rectal electroejaculation and testicular biopsies at 5 1/2 years of age confirmed two cases of testicular hypoplasia. Semen evaluation, testicular biopsies and analysis of serum testosterone levels at 6 1/2 years of age indicated normal testicular morphology and function in all DES-exposed males as compared with colony controls. Our study, therefore, suggests that DES may affect maturation of the reproductive tract as indicated by a delay in the normal breakdown of preputial adhesions in addition to gross and microscopic evidence of testicular hypoplasia during the postpubertal period between 4 1/2 and 5 1/2 years of age. Further observations on breeding performance and fertility are required to evaluate the long-term effects of DES in this species.

Animals↗

PubMed1981

Visualization by light and scanning electron microscopy of reproductive tract lesions in female mice treated transplacentally with diethylstilbestrol.

Pregnant female mice were exposed to diethylstilbestrol or 11 beta-methoxy-17 beta-estradiol on Days 9 to 16 of gestation. The female offspring of these animals were then examined for reproductive tract abnormalities. Scanning electron microscopic and histological evaluation of these specimens demonstrated reproductive tract lesions in all treatment groups when compared to matched control mice. These lesions included apparent displacement of the squamocolumnar junction, uterine squamous metaplasia, atypical uterine cell surface specializations, protrusions of uterine cells, vaginal and cervical papillary growths, enlarged uterine cervix, abnormal vaginal and uterine folding patterns, female hypospadias, and the presence of vaginal concretions. Scanning electron microscopic observations proved particularly useful in studying lesions which involved the disruption of the normal structure and shape of the reproductive tract and the displacement of cell types.

Animals↗