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PubMed1980

Studies on the methylation of diethylstilbestrol by preparations of rat liver.

The methylated metabolites of diethylstilbestrol (DES) were formed by incubation with S-adenosyl-(3H-methyl)-L-methionine (SAM) and preparations of rat liver. Formation of the O-methyl-catechol metabolite required the 10,000 g supernatant fraction, NADPH and SAM. The nonionic detergent Triton X-100 (0.025%, v/v) did not affect the activity of the methyltransferase but stimulated glucuronyltransferase and inactivated the mixed function oxidases. Thus, incubation with Triton abolished methylation of DES by the 10,000 g supernatant fraction, but methylation and glucuronidation of DES was observed when incubated with microsomes and NADPH and reincubated with Triton, soluble fraction, UDP-glucuronic acid and SAM. Since DES itself was not methylated by the soluble fraction, the results suggest that DES is oxidized by mixed function oxidases to a catechol which is methylated and then glucuronidated. Results of reincubation studies support this sequence. Methylation does not impair glucuronidation of the catechol but glucuronidation prevents its methylation.

Animals↗

PubMed1981

Contrasting effects of diethylstilbestrol and estradiol on contraction of isolated rat aorta.

Diethylstilbestrol (DES, 1 X 10(-6) M) inhibited norepinephrine (NE)-induced contractions of isolated rat aortic strips only at low doses of NE in contrast to estradiol-17 beta (1 X 10(-5) M) which depressed only the response to high doses. The degree of inhibition increased over a period of 90 min exposure to the estrogens. Microsomes accumulated process appears to be gradual requiring many minutes which may explain the gradual increase in intensity of the inhibitory effect with increased time of exposure to DES. The contrasting inhibitory effects of DES and estradiol in rat aorta may be due to non-homogeneous solution of these drugs in smooth muscle plasma membranes. DES, but not estradiol, caused contraction of isolated aortic strips prior to the onset of inhibition. This contraction showed fade and tachyphylaxis, was antagonized by alpha-adrenergic blockers, and was enhanced by prior treatment of the strips with NE. Thus, DES but not estradiol is capable of mobilizing NE from storage sites in rat aorta.

Animals↗

PubMed1985

Effects of maternal administration of diethylstilbestrol and estradiol on the newborn guinea pig.

The subcutaneous injection of diethylstilbestrol (2.5 micrograms/day) into pregnant guinea pigs from the 28th or 40th day to term resulted in an accelerated tempo of differentiation of the genital tract of the female offspring at birth, as well as intense estrogenic stimulation. Estradiol (50 micrograms per day) injected over the same period caused insignificant estrogenic stimulation in the newborn. The normal embryogenesis of the genital tract is described and a pattern of caudocranial differentiation identified. The normal genital tract is described as a basis for the analysis of results in the newborn. Comparative studies in other animals are discussed.

Animals↗

PubMed1986

Estrogen participation in induction of cervicovaginal adenosis-like lesions in immature mice exposed prenatally to diethylstilbestrol.

A high incidence of vaginal adenosis-like lesions (ADL, 67%) was found in 30-day-old offspring of ICR/JCL mice given 4 daily subcutaneous injections of 2,000 micrograms diethylstilbestrol (DES) on days 15-18 of gestation. The prenatally DES-exposed mice and the controls ovariectomized at 10 days of age were given 5 daily subcutaneous injections of 10(-4), 10(-3), 10(-2), 10(-1), or 1 micrograms 17 beta-estradiol (E2), respectively, starting at 25 days of age. ADL was never observed in the age-matched controls given prepubertal injections of any E2 dose. In contrast, high incidences of ADL (63-100%) were found in the vaginal fornix and upper vagina of 30-day-old DES mice receiving prepubertal injections of 10(-3)-1 micrograms E2/day, whereas in DES mice given prepubertal injections of the vehicle alone and a lower daily dose of 10(-4) micrograms E2, incidences were nil and 25%, respectively. Mitotic figures were found in the columnar epithelium with ADL, although the rate was lower than in the ADL-freed stratified epithelium. It is suggested, therefore, that an ovarian hormone (probably estrogen) participates in the prepubertal induction of ADL in DES mice.

Animals↗

PubMed1987

Delayed effects of prenatal or postnatal exposure to diethylstilbestrol in the adult female guinea pig.

Of 25 mature female guinea pigs exposed transplacentally to diethylstilbestrol (DES) for more than 20 days before term, 8 showed abnormal changes in the genital tract (stimulation of the epithelium and stroma, cystic glandular hyperplasia of the endometrial glands near the junction of the upper endocervix and endometrium) and 9 showed severe changes (cystic glandular hyperplasia of the endometrial glands throughout the corpus uteri and cornua, squamous metaplasia). Hyperkeratosis of the vulvar and nipple skin was also observed. No neoplastic changes were observed with one exception at 14 months in one ovary. Prenatal exposure to DES for less than 15 days before term or after birth for 3 days failed to result in abnormal changes in the adults. Prenatal exposure to estradiol for more than 20 days also was without effect in the adult, despite the higher tolerated doses given to the mothers. Cycling activity as judged by vaginal opening was abnormal in all experimental groups, suggesting a derangement of the pituitary-hypothalamic function not specifically related to DES exposure. It was concluded that there is a critical period of exposure of the Müllerian duct- and sinus-derived tissues with respect to the delayed effects of prenatal exposure to DES, which is estimated on the basis of embryological studies to range from the 28th to about the 45th day of gestation.

Animals↗

PubMed1989

In utero exposure of mice to diethylstilbestrol alters neonatal ovarian follicle growth and development.

The prenatal exposure of mice to diethylstilbestrol (DES, 10 micrograms/kg on day 15 of gestation) caused both quantitative and structural alterations in ovarian follicles within the neonatal ovary. At birth, control ovaries consisted of small type 1 and 2 ovarian follicles located in the ovarian cortex. By postnatal day 7, ovarian follicle development had advanced to the type 4 stage with larger follicles located within the ovarian medulla. In DES-exposed animals, ovarian follicle maturation was advanced with type 3b and 4 follicles appearing 24 h prior to their appearance in control animals. Also, type 5 ovarian follicles were present on postnatal day 6 in experimental animals but were never seen in control animals. In addition to an alteration in ovarian follicle dynamics, the diameter of individual ovarian follicles was transit time between the various stages of follicular development which results in a greater number of developmentally advanced ovarian follicles being present during neonatal ovarian development. The mechanism by which prenatal exposure to DES alters ovarian follicle dynamics during neonatal development is not known.

Animals↗

PubMed1992

Failure to detect a second-generation effect in female mice after neonatal treatment with an estrogen (diethylstilbestrol).

Inbred female mice of the NMRI strain were treated subcutaneously with 5 micrograms diethylstilbestrol (DES) in olive oil or vehicle only for the first 5 days after birth. One group of DES-treated females was killed at the age of 8-12 weeks, and the uterine cervix and adjacent parts of the vagina and uterine horns prepared for histological studies. In all preparations, the cervical epithelial lining contained regions with heterotopic columnar epithelium (HCE) along 69-100% of the length of the common cervical canal. Ovaries from neonatally DES-treated females were grafted to 8-week-old ovariectomized control hosts and these hosts were mated to control males 2 weeks later. The hosts gave birth to normal-sized litters. The female offspring from these litters had a normal cervical epithelial lining and, in turn, gave birth to normal-sized litters. These results indicate that treatment of neonatal female mice with DES does not affect the female germ cells as far as concerns factors associated with the development of HCE or reduced fertility in the next generation.

Animals↗

PubMed1979

Effect of diethylstilbestrol on replication and transformation by human herpesviruses.

Human embryo fibroblasts treated with diethylstilbestrol (DES) gave rise to slightly increased plaque production by cytomegalovirus (CMV): plaques were also slightly larger in treated cells when compared to those in untreated cultures. There was no significant enhancement of plaque production by herpes simplex virus (HSV) types 1 and 2 in the human cells or in primary rabbit kidney cells treated with DES. Growth analyses of HSV and CMV in DES-treated cells failed to reveal enhancement of virus production when compared to untreated cells. The frequency of biochemical transformation of mouse cells deficient in thymidine kinase (TK) to the TK+ phenotype by HSV was markedly enhanced when cells were pretreated with DES. TK+-transformed colonies arising from DES-treated cells were also larger than those derived from untreated cultures. These reveal that DES increases susceptibility of human cell lines to CMV infection and enhances efficiency of biochemical transformation of mouse cells by HSV.

Animals↗

PubMed1994

Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol.

In addition to its tumor-promoting activity in hormone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were formed during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus formation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the G0/G1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of S and G2 transit may involve a process ultimately leading to micronucleus formation.

Animals↗

PubMed1980

Estrogen target cells in the larynx: autoradiographic studies with 3H-diethylstilbestrol in fetal mice.

Serial sections from 16-day mouse embryos from mothers injected with 3H-diethylstilbestrol were processed for autoradiography. The distribution, in the laryngeal region, of cells with nuclear concentrations of radioactivity was analyzed. Estrogen receptor cells were found in the mesenchyme of the vocal cords and lateral to the laryngeal aditus. The embryological and oncological implications of these findings are discussed.

Animals↗

PubMed1984

Increase of sister chromatid exchange formation induced by diethylstilbestrol.

The latent appearance of genital tract tumors in young women is highly correlated with prenatal exposure to synthetic estrogens such as diethylstilbestrol (DES). To extend the information on the mutagenic effect of DES, the frequency of sister chromatid exchange (SCE) was determined in bone marrow cells of Sprague-Dawley rats and in cultured FR3T3 rat fibroblasts. In this study a significant increase of SCE frequency after the application of different concentrations of DES could be observed both in vivo and in vitro.

Animals↗

PubMedDate not supplied

Advanced primary clear cell carcinoma of the vagina not associated with diethylstilbestrol.

BACKGROUND: Primary vaginal clear cell carcinoma occurs in young women exposed to diethylstilbestrol (DES) in utero. Primary vaginal clear cell carcinoma not associated with DES is very rare. We report the clinicopathologic and cytopathologic features of a patient with advanced, sporadic primary vaginal clear cell carcinoma with metastases to liver, lung and paraaortic lymph nodes. CASE: A postmenopausal, 63-year-old woman presented to our department with genital bleeding. A hemorrhagic tumor found in the vagina was diagnosed as a clear cell carcinoma by cytopathologic examination of the tumor smear and by histopathologic examination of a biopsy specimen. A chest radiograph revealed multiple lung metastases, and metastases to the liver and paraaortic lymph nodes were noted on computed tomography and magnetic resonance imaging. The tumor was diagnosed as primary clear cell carcinoma of the vagina, stage IVb (FIGO) based on a normal cytopathologic examination of the cervix, endometrium and ascites; normal appearance of the uterus, ovaries and kidneys on magnetic resonance imaging; and absence of detectable tumor in the urinary tract. The patient died of respiratory failure 31 days after hospitalization. The tumor demonstrated overexpression of p53 protein and did not show microsatellite instability. CONCLUSION: This patient was the second reported Japanese woman with advanced primary vaginal clear cell carcinoma not associated with DES.

Adenocarcinoma, Clear Cell↗

PubMed1988

Physical and psychological problems associated with exposure to diethylstilbestrol (DES).

The synthetic hormone diethylstilbestrol (DES) was widely prescribed between 1943 and 1971 to minimize pregnancy complications. It has caused serious physical and psychological damage to the women who took it and to their offspring. DES-exposed mothers may suffer a higher incidence of breast cancer, their exposed daughters are at risk for reproductive tract cancers and infertility, and their exposed sons are more likely to have genital abnormalities and reproductive dysfunction. Psychiatric disorders among DES-exposed persons are reportedly twice as common as for nonexposed persons, with anger, anxiety, low self-worth, identity confusion, and guilt the most frequent symptoms. The author describes therapeutic interventions designed to alleviate these problems.

Adaptation, Psychological↗

PubMed2004

Apoptosis in the epididymal epithelium of adult male golden hamster exposed to diethylstilbestrol.

Apoptosis in the testis and prostate exposed to disrupters of endocrine function, including diethylstilbestrol (DES), during neonatal or postnatal periods has repeatedly been demonstrated, but not in the mature epididymis. We investigated the effects of DES, a potent and synthetic estrogen, on apoptosis in the adult. Adult male golden hamsters received an SC injection of DES and were then sacrificed to collect epididymides after 1, 4, or 7 days of treatment. A significant decrease in epididymal weight and an increase in apoptotic cells were shown on the first day after DES injection. Flow cytometry showed that DES treatment (1 mg/kg) for 1, 4, or 7 days induced significant apoptosis both in the caput and the cauda epididymides. Greater numbers of apoptotic cells were detected in the caput than in the cauda at a fixed time after DES treatment. Serum levels of testosterone decreased markedly within 24 hr after DES administration, reaching undetectable levels of 0.1 ng/ml at 4 days and thereafter. These results indicate that DES administration can increase epididymal apoptosis with a decrease in serum testosterone levels. Because DES used to be injected into domestic animals, adult males also have a chance to take this substance through food. Our study indicates that exposure to DES in adults is as toxic as that in the perinatal period.

Animals↗

PubMedDate not supplied

Abnormal cell differentiation and p21 expression of endometrial epithelial cells following developmental exposure to diethylstilbestrol (DES).

Gene expression relevant to abnormal cell differentiation and altered cell cycle in endometrial epithelial cells was investigated immunohistochemically in developing mouse uteri exposed neonatally to diethylstilbestrol (DES). Female CD-1 mice were given daily s.c. injections of 2 microg of DES in corn oil or were given corn oil alone (control) at 1-5 days of age and euthanatized at 5, 6, 7, 8, 15, and 22 days of age. The endometrial epithelial cells of DES-treated mice at 5-8 days of age showed enhanced staining intensity for the estrogen receptor alpha (ER alpha), whereas the stromal cells showed decreased staining reaction; the epithelial cells showed that the protein encoded by the c-fos proto-oncogene, which plays a key role in regulating diverse estrogen-related cellular differentiation patterns, was enhanced. These cells also showed increased expression of lactoferrin, a sensitive protein marker of estrogen exposure, although the staining intensity decreased after exposure ended. The stain for p21 protein, a mitotic inhibitor which suppresses cyclin-dependent kinase activity, showed frequent positively stained cells in DES-treated mice at 5-15 days of age, whereas no accumulation of p53 protein of either wild or mutant type was detected immunohistochemically in these cells. These results indicate that suppressed cell cycle activity of endometrial epithelial cells and abnormal estrogen-related differentiation at the developmental stage following neonatal DES exposure may be caused, in part, by transient altered expression of ER alpha and expression of the p21 gene, which appears to be induced by a p53-independent mechanism.

Animals↗

PubMedDate not supplied

Effects of neonatal diethylstilbestrol (DES) exposure on morphology and growth patterns of endometrial epithelial cells in CD-1 mice.

The effects of neonatal diethylstilbestrol (DES) exposure on the morphology and proliferating patterns of endometrial epithelial cells were investigated at various stages of development in mice. Female CD-1 mice were given daily subcutaneous injections of 2 micrograms of DES in corn oil or corn oil alone (control) at 1-5 days of age and were killed at 5, 6, 7, 8, 15, and 22 days of age. At 5 days of age, the uteri of DES-treated mice had expanded lumina and undulated luminal surfaces lined by slightly elongated epithelial cells. At 6-8 days of age, marked infolding of clusters of hypertrophic elongated luminal epithelial cells was present; uteri had disorganized endometrial stromal and myometrial layers. At 15 and 22 days of age, the tissues from DES-treated mice had decreased numbers of endometrial glands, minimal stromal fibrosis, and smaller uterine horns than did the controls. Ultrastructurally, the endometrial epithelial cells of DES-treated mice at 5 and 8 days of age had distorted nuclei with condensed matrix and abundant secretory granules associated with rough endoplasmic reticulum and Golgi apparatus. At 8 days of age, an accumulation of fingerlike cytoplasmic processes that extended into the separated intercellular spaces and along the basal aspects of the endometrial epithelial cells were also observed. At 5-8 days of age, the proliferative activity of endometrial epithelial cells in DES-treated mice, identified by bromodeoxyuridine labeling, was significantly lower (10.5-1.7%) than that of the controls (25.5-19.8%). In situ analysis of endometrial luminal epithelial cells for DNA fragmentation representing apoptosis revealed < or = 0.1% and > 10% in the DES-treated and control mice at 5-8 days of age, respectively. The data show that cell cycle kinetics, in addition to changes in morphology, are altered in the developing mouse uterus following neonatal exposure to DES.

Animals↗

PubMed2006

Global gene expression in mouse vaginae exposed to diethylstilbestrol at different ages.

Estrogens regulate proliferation and differentiation of cells in target organs such as the female reproductive tract. In mature mice, estrogens stimulate cell proliferation, whereas ovariectomy results in atrophy of the female reproductive tract. In contrast, perinatal exposure to estrogens, including diethylstilbestrol (DES), induces persistent, ovary-independent vaginal stratification and cervico-vaginal tumors later in life. These effects are due to altered cell fate following DES exposure during a critical developmental period. The detailed mechanisms underlying the reversible and irreversible cell proliferation in vaginae induced by DES at different ages has not been clarified. Therefore, we examined differences in gene expression pattern using DNA microarray analysis in mouse vaginae 6 hrs after a single injection of 2 mug DES per gram of body weight, and proliferation of vaginal epithelial and stromal cells 24 hrs after the injection at postnatal days (PNDs) 0, 5, 20, and 70. After DES stimulation, vaginal epithelial and stromal cells showed cell proliferation at PNDs 20 and 70, and at PNDs 0 and 5, respectively. DNA microarray analysis exhibited 54 DES-induced genes and 9 DES-repressed genes in vaginae at PND 0, whereas more than 200 DES-induced genes were found in vaginae at PNDs 5 and 20, and 350 genes at PND 70. Clustering analysis of DES-induced genes in the vaginae at different ages revealed that genes induced by DES at PND 5 were closer to the adult type than that of PND 0. Genes related to keratinocyte differentiation, such as Gadd45alpha, p21, 14-3-3 sigma, small proline-rich protein 2f (Sprr2f), and Krupple-like factor 4 (Klf4), were induced by DES. The number of DES-induced genes during the critical period, PND 0, was smaller than those found after the critical period. These results give insight toward understanding the molecular mechanisms underlying the critical period in mouse vaginae.

Animals↗

PubMed1996

Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.

PURPOSE: Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects. PATIENTS AND METHODS: The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization. RESULTS: Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040). CONCLUSION: As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.

Administration, Oral↗