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PubMed1987

Testicular tumors in mice exposed in utero to diethylstilbestrol.

Treatment of pregnant women with diethylstilbestrol (DES) is associated with the subsequent development of reproductive tract abnormalities such as epididymal cysts, retained hypotrophic testes and sperm abnormalities in their male offspring. It recently has been suggested that prenatal DES exposure is associated with development of testicular seminoma in humans. Studies of in utero exposure of laboratory animals to DES are few, but previous reports from our laboratory have described several abnormalities in the reproductive tract of the mouse following prenatal DES exposure. To study the possible association of testicular tumors and prenatal DES exposure in mice, pregnant outbred CD-1 mice were injected subcutaneously with daily doses of DES (100 micrograms./kg.) on days nine through 16 of gestation. DES-exposed and age-matched control male mice were sacrificed at 10 to 18 months of age and examined for testicular lesions. In addition to the nonmalignant abnormalities reported in previous studies such as 91% cryptorchidism and degenerative changes, interstitial cell tumors were observed in nine mice among 277 mice treated prenatally with DES. Two of these lesions were benign tumors and five were interstitial cell carcinomas. Rete testis adenocarcinoma was seen also in 5% of these DES-treated animals and is described in another report. The overall incidence of testicular tumors is 8% in DES-exposed male mice. No comparable lesions were seen in 122 control male mice. These results suggest that the testicular lesions that can occur following prenatal DES exposure include neoplasia. The combined prevalence of DES-induced tumors of the corpus testis and rete testis in mice suggests the male offspring may be more at risk for developing carcinoma of the reproductive tract than the female offspring.

Animals↗

PubMed1983

Effect of diethylstilbestrol on bladder contractility in male rats.

The effect of diethylstilbestrol (DES) on bladder contractility was studied in vitro in 8 rats while 5 untreated animals were used as normal controls. Of the treated animals, 4 received 0.05 mg./day of DES during 8 weeks while another 4 were treated for 14 weeks with the same dose. We studied the animals by cutting consecutive rings from each bladder and testing them in a muscle chamber, under conditions of maximal electrical stimulation which had been previously determined in 3 animals. Parameters that produced maximal contractions were: 100 V, 40 Hz, and 2 msec. For each ring, we obtained full force-length relationships by stretching the rings in successive increments until length of maximal active force development was reached. For each bladder, alternate rings were tested in the muscle chambers while the remaining rings were used to determine collagen percentage with Woessner assay. In all animals, the ring with the largest diameter which was obtained from the widest portion of the bladder gave the highest contraction. The maximal active force of this ring was taken as a measure of contractility of the bladder. For controls, the maximal active force was 7.30 +/- 0.3 g. After 8 weeks of DES treatment, it decreased to 5.9 +/- 0.79 g and after 14 weeks, it further decreased to 2.15 +/- 0.99 g. The reduction in active force from controls after 8 and 14 weeks were statistically significant. Passive force and collagen content, however, did not change after either 8 or 14 weeks. In conclusion, these data show that DES decreases bladder contractility in male rats without affecting passive forces and muscle-collagen ratio.

Animals↗

PubMed1982

Effects of diethylstilbestrol and estramustine phosphate (Estracyt) on lymphoid cell populations and mitogen responsiveness in male mice.

Concentrations of diethylstilbestrol phosphate (DES-P) and estramustine phosphate (EMP) above 10(-5) M in cultures of spleen lymphocytes from adult male mice resulted in a dose related inhibition of both Con A and LPS induced lymphocyte proliferation. Male mice injected with 5.6 mg./kg. DES daily for 7 days had a significantly reduced responsiveness to both Con A and LPS compared to mice injected with olive oil only. Spleen lymphocytes from male mice treated with 100 mg./kg. EMP showed a reduction of Con A induced mitogenesis whereas they exhibited a significantly enhanced response to LPS. The effects of DES and EMP on Con A and LPS induced blastogenesis were abolished within 2 weeks after cessation of treatment. DES treatment resulted in preferential depletion of splenic and lymph node T lymphocytes and a disproportionate T lymphocyte subpopulation with respect to Ly subclasses. Exposure to 30 or 100 mg./kg. EMP resulted in a dose related loss of mononuclear cells both in spleen and lymph nodes. T lymphocytes predominantly of the Ly 1 phenotype were most sensitive to EMP. Co-cultures of spleen lymphocytes from normal mice and Mitomycin C blocked spleen cells from either normal of treated mice (DES or EMP) gave no convincing evidence of suppressor cell activity in the population of spleen mononuclear cells.

Animals↗

PubMed1999

Effect of perinatal synthetic steroid hormone (allylestrenol, diethylstilbestrol) treatment (hormonal imprinting) on the bone mineralization of the adult male and female rat.

Neonatal treatment with allylestrenol or diethylstilbestrol (DES) reduced the bone mineral content (BMC/bw) of the adult (four months old) female rats, without influencing bone mineral density (BMD/bw). In males these neonatal treatments elevated BMC and BMD alike. Ovariectomy alone decreased BMC and BMD alike; however the neonatal hormone treatments did not influence this reduced value. Ovariectomy of two months old animals increased body weight without the influence of neonatal hormone treatments. In adult males, the body weight was reduced significantly by neonatal DES and non-significantly by neonatal allylestrenol treatment. The experiments call attention to the possible human bone-effects of allylestrenol, which was used in the last decades as medication protecting endangered pregnancies.

Absorptiometry, Photon↗

PubMed1999

Induction of multiple microtubule-organizing centers, multipolar spindles and multipolar division in cultured V79 cells exposed to diethylstilbestrol, estradiol-17beta and bisphenol A.

Inducibility of multipolar spindles and multipolar division by diethylstilbestrol (DES) and estradiol-17beta (E2) was investigated in terms of the mechanism of induction of aneuploidy by the estrogens. DES, E2 and bisphenol A (Bp-A), a structural analogue of DES, caused mitotic arrest and aberrant spindles, such as tripolar and multipolar spindles, in a concentration-dependent manner. Gamma-tubulin, a well-characterized component of microtubule-organizing centers (MTOCs), was co-localized with the aberrant spindles induced by estrogens and Bp-A. The number of gamma-tubulin signals in the mitotic cells coincided with that of the aberrant spindles and rose with an increasing concentration of the chemicals. The incidence and location of gamma-tubulin in interphase cells were not influenced by the chemicals. These results suggest that multiple MT nucleating sites were induced by the estrogens and Bp-A during the transition from interphase to the mitotic phase. DES, E2 and Bp-A induced multipolar division in a concentration-dependent process associated with the induction of aneuploidy.

Aneuploidy↗

PubMed2000

Office systems intervention to improve diethylstilbestrol screening in managed care.

OBJECTIVE: To examine the effectiveness of a comprehensive office systems intervention for improving identification of diethylstilbestrol (DES) exposure, a low-incidence condition with potentially severe consequences. METHODS: We developed a comprehensive office systems intervention to facilitate screening and follow-up for women exposed to DES in utero, consisting of a DES toolkit and the clinical and administrative education necessary to use the tools effectively. The intervention was implemented in the internal medicine and obstetrics-gynecology departments at six free-standing health centers in a Boston-area staff-model health maintenance organization. Intervention sites were matched and paired with a comparison group of centers. Intervention effectiveness was assessed through pretest and posttest surveys of clinicians, medical record review of 3900 women, and review of a computerized medical records data base. RESULTS: There was significantly higher DES awareness and knowledge among clinical staff at intervention sites. Documentation of DES exposure in the medical record ranged from 1.14 to 2.31 times greater at intervention sites than in matched comparison sites, and rates of DES code use in pregnancy were 1.91 to 3.61 times greater. CONCLUSIONS: The office systems intervention improved documentation of DES exposure in a managed care environment. Because this approach was designed to accommodate the limited time allotted for each patient visit, it not only improved DES screening but could also serve as a model for integrating screening for other low-prevalence but potentially serious conditions into routine care.

Adult↗

PubMed2002

Findings in female offspring of women exposed in utero to diethylstilbestrol.

OBJECTIVE: To examine a group of women (third-generation daughters) whose mothers were exposed in utero to diethylstilbestrol (DES) and compare their findings on pelvic examination with those noted in their mothers. METHODS: Letters were mailed to women documented to have been exposed in utero to DES who had given birth to a female offspring, inviting them to have their daughters come in for a detailed history and pelvic examination. Records of the mothers whose daughters appeared for examination were reviewed, and findings noted at the time of their initial examination were recorded. Detailed pelvic examination of the third-generation daughters included colposcopic examination and iodine staining of the vagina and cervix and Papanicolaou smear. The findings observed in these women were compared with those noted in their mothers at the time of their mothers' first examination. RESULTS: Twenty-eight third-generation daughters were examined. Three of the daughters were delivered from one mother. Review of the mothers' records indicated that 16 (61.5%) of the mothers exposed to DES during their pregnancy demonstrated structural changes of the cervix, upper vagina, or vaginal epithelial changes consisting of adenosis, nonstaining vaginal epithelium after application of iodine solution, or white epithelium within the vagina. None of the daughters were found to have changes usually associated with DES exposure. CONCLUSION: The absence of abnormalities in the lower genital tract in third-generation women compared with the high frequency of these abnormalities in their mothers suggests that third-generation carryover effects of in utero DES exposure are unlikely.

Adenocarcinoma, Clear Cell↗

PubMed1981

Synthesis of metabolic intermediates of diethylstilbestrol.

This report details the synthesis of 1) 3,4,4'-trihydroxy-alpha, alpha'-diethyl-trans-stilbene; 2) 3,4-bis-(p-hydroxyphenyl)-trans-3-hexenol; 3) 3,4-bis-(p-hydroxyphenyl)-2,4-cis,cis-hexadienol; 4) 3,4-bis-(3'-methoxy-4'-hydrophenyl)-trans-3-hexene; 5) 3,4-bis-(3',4'-dimethoxyphenyl)-trans-3-hexene. These compounds are suspected metabolites of diethylstilbestrol.

Dienestrol↗

PubMed2000

Promotive effect of diethylstilbestrol on urethan-induced mouse lung tumorigenesis.

The effect of diethylstilbestrol (DES) on urethan-induced mouse lung tumorigenesis was assessed by a single intraperitoneal injecting of urethan (50 mg/kg) or/and multi intramuscular injecting of DES (5 or 50 mg/kg). All mice were sacrificed 18 weeks after administration, and the lung tumors were examined histopathologically. DES did not produce an elevated lung tumor response when administered alone, but it produced a statistically significant enhancement of incidence of tumors, average number of tumors, incidence of cancers and constituent ratio of malignant tumors when given in conjunction with urethan. The results indicated that DES may be a promoter in lung tumor formation.

Animals↗

PubMed1982

Normal development of the human female reproductive tract and alterations resulting from experimental exposure to diethylstilbestrol.

An in vivo model is described for the study of human uterovaginal development in the presence and absence of the teratogenic drug diethylstilbestrol (DES). Intact reproductive tracts from fragments of 29 human embryos and fetuses 5.0 to 17.7 weeks of age obtained after dilatation and curettage were grown for four weeks in vivo in athymic (nude) mice that were either untreated (control) or implanted subcutaneously with a DES pellet. Control specimens grown in vivo continued their anticipated morphogenesis for equivalent in-utero ages; the normal processes observed included fusion of the paired embryonic müllerian ducts into a single uterovaginal canal, stratification of endometrial and tubal mesenchyma into inner (presumptive endometrial stroma) and outer (presumptive myometrium) layers; plication of tubal and endometrial mucosa; uterine gland formation; and stratification (transformation) of the simple columnar epithelium of the vagina and cervix into a stratified squamous plate. Specimens exposed in vivo to DES exhibited anomalies, many of which mimicked those observed clinically in young women exposed prenatally to DES. Glandular epithelium (adenosis) was found in the vagina. The upper genital tract was malformed; its growth was stunted, and the inner and outer stromal layers of the uterine corpus and fallopian tubes failed to segregate. The authors conclude that the in vivo model that they describe, with its built-in controls, provides a valid approach for examining the dynamics of morphogenesis and cytodifferentiation in developing human genital tracts under experimentally regulated conditions.

Animals↗

PubMed1986

Vaginal adenosis in women born prior to the diethylstilbestrol era.

Vaginal adenosis was evaluated in 41 women, all of whom had been born prior to the diethylstilbestrol (DES) era, and compared with the adenosis commonly encountered in DES-exposed progeny. The patients were 24 to 88 years of age (median, 44 years). Six of the women were symptomatic, and in four of these six the glands were enmeshed in a marked inflammatory infiltrate. In an additional 26 women the adenosis was discovered as incidental, nonsymptomatic macroscopic nodules or cysts. The remaining nine cases of adenosis were discovered by pathologists. Three types of epithelia characterized the glands: mucinous, tuboendometrial, and embryonic. Mucinous columnar cells resembling the lining of the normal endocervix and tuboendometrial cells resembling the lining of the normal fallopian tube or endometrium constituted the glands exclusively in 22 and eight specimens, respectively, and as a mixture in seven. The glands lined by mucinous cells most often presented clinically as cysts or nodules. The specimens composed of tuboendometrial cells were most often discovered on microscopic examination. The third type of epithelium, composed of embryonic columnar cells, was encountered in four specimens. These glands, less than 30 micron in greatest diameter, were located at the junction between the lamina propria and the squamous epithelium, and were incidental microscopic findings. It is concluded that the microscopic appearances of adenosis in women born prior to the DES era are identical to those encountered in young women exposed in utero to DES.

Adult↗

PubMed1987

Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract.

The potential estrogenicity and teratogenicity of triphenylethylene antiestrogens were examined in 54 genital tracts isolated from 4- to 19-week-old human female fetuses and grown for 1 to 2 months in untreated athymic nude mice or host mice treated by subcutaneous pellet with the antiestrogens clomiphene and tamoxifen or the synthetic estrogen diethylstilbestrol (DES). In specimens grown to a gestational age equivalent of 15 weeks or less, the vagina and urogenital sinus were lined by an immature squamous epithelium, which were similar in both drug-treated and untreated specimens. Proliferation and maturation of the squamous vaginal epithelium were observed in specimens treated with clomiphene, tamoxifen, or DES only when grown to a gestational age equivalent of 16 weeks or more. Formation of endometrial and cervical glands proceeded in 87 per cent (13 of 15) of control specimens grown to a gestational age equivalent of 13 weeks or more in untreated hosts. By contrast, age-matched drug-treated specimens contained glands in only 44 per cent (12 of 27) of specimens. In the developing uterine corpus of untreated controls, the uterine mesenchyme segregated into inner (endometrial stroma) and outer (myometrial) layers; whereas in drug-treated specimens, condensation and segregation of the mesenchyme were greatly impaired. The fallopian tube was also affected by clomiphene and tamoxifen (and to a lesser extent by DES) in that its epithelium was hyperplastic and disorganized. The complex mucosal plications characteristic of the fallopian tube were also distorted in drug-treated specimens. These results emphasize the heretofore unrecognized estrogenicity and potential teratogenicity of triphenylethylene antiestrogens on the developing human genital tract and emphasize the need for caution to prevent inadvertent exposure of the developing fetus to these compounds.

Abnormalities, Drug-Induced↗

PubMed1988

Temporal and spatial factors in diethylstilbestrol-induced squamous metaplasia of the developing human prostate.

The effects of exogenous estrogen on the developing human prostate were examined in human fetal prostatic rudiments grown for 1 month as subcapsular renal grafts in athymic male nude mice treated with diethylstilbestrol (DES). Prostatic rudiments grown in untreated (control) hosts exhibited normal ductal morphogenesis, growth, and secretory cytodifferentiation. Squamous metaplasia was observed rarely in controls (2 of 22). Conversely, squamous metaplasia was observed in the prostatic utricle and urethra of all 17 specimens grown in DES-treated hosts. Proximal and distal prostatic ducts exhibited DES-induced squamous metaplasia in 13 and 12 of the specimens, respectively. When present, metaplastic changes were mild in the distal ducts. The distribution and intensity of metaplasia were related to the age of the specimen during the period of DES exposure. In specimens grown in DES-treated hosts to a gestational age equivalent of 16.5 weeks or less, squamous metaplasia was only seen in the prostatic utricle and urethra; however, in specimens grown to a gestational age equivalency of 17 weeks or more, squamous metaplasia was observed in the prostatic ducts as well. The nonuniform distribution of estrogen-induced squamous metaplasia within the developing prostatic ductal system emphasizes a regional and age-dependent susceptibility to exogenous estrogens in proximal ductal areas (near the urethra) as compared with distal ductal regions of the developing human prostate.

Animals↗

PubMed1999

The avian egg as a test system for endocrine disrupters: effects of diethylstilbestrol and ethynylestradiol on sex organ development.

Many environmental contaminants are known or suspected to interfere with hormonal function in animals. In vivo test methods to detect and characterize chemicals that disrupt the endocrine system are therefore urgently needed. In this study, we assessed the usefulness of abnormalities of the reproductive organs as test endpoints for estrogenic activity of xenobiotics in Japanese quail embryos. Two synthetic estrogens, diethylstilbestrol (DES) and ethynylestradiol (EE2), were injected into the yolks of embryonated eggs. At a dose as low as 2 ng EE2/g egg, all male embryos became feminized, containing ovary-like tissue in the left testis. The extent of feminization of the testes was determined by measuring the relative area of the ovary-like component. Persistent Müllerian ducts (oviducts) in male embryos, and malformations of the Müllerian ducts in females occurred at 2 ng EE2/g egg and higher doses. DES was approximately one-third to one-tenth as potent as EE2. The morphological changes studied were dose-dependent, indicating that they are useful as test endpoints for estrogenic activity. Feminization of the left testis in males proved to be the most sensitive endpoint. We propose the quail egg as a simple in vivo test system for estrogenic compounds.

Androgen-Insensitivity Syndrome↗

PubMed2003

Diethylstilbestrol and tetrahydrochrysenes are calcium channel blockers in human platelets: relationship to the stilbene pharmacophore.

The effects of compounds with the stilbene pharmacophore [diethylstilbestrol (DES), DES derivatives, tetrahydrochrysene (THC), and THC derivatives] were examined for their ability to inhibit thrombin-induced Ca(2+) influx in human platelets. DES derivatives (DES dimethyl ether, DES dipropionate, dienestrol, and hexestrol) had lower inhibitory activity than DES. Esterification of DES with the bulky monobenzyl group eliminated inhibitory activity. Unsubstituted THC diol had the lowest inhibitory activity in the series of the THC derivatives bearing substituents in the 5,11 positions. These derivatives, either diethyl or dipropyl, cis or trans, were potent inhibitors of thrombin-induced [Ca(2+)](i) elevation (near 100% inhibition at 10 microM). Therefore, stilbene pharmacophore having bulk out of the plane of the double bond (from the twisting of the two aromatic rings or from addition of all substituents) seems to be requirement for the inhibitory activity. Free hydroxyl groups are also required for inhibitory activity, most likely for hydrogen bonding, since trans-diethyl tetrahydrochrysene dimethyl ether was inactive. Compounds bearing ethyl substituents (DES and THC derivatives) inhibited thrombin-induced release of calcium from the endoplasmic reticulum. These compounds also inhibited thapsigargin-induced Ca(2+) influx. This result implies that these compounds also block store-operated Ca(2+) influx directly, as well as internal Ca(2+) release. Compounds without ethyl substituents (trans-resveratrol, genistein, daidzein, and THC diol) only inhibited calcium influx into platelets.

Adult↗

PubMed2002

Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study.

BACKGROUND: Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. METHODS: We did a cohort study of all sons of a Dutch cohort of 16284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. FINDINGS: 16284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21.3 [95% CI 6.5-70.1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1.8, 0.6-5.7). INTERPRETATION: Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.

Cohort Studies↗

PubMed1977

Stilboestrol (diethylstilbestrol) and the risk of ovarian cancer.

A follow-up survey of 908 women who had received 'Premarin' (conjugated equine oestrogen) for menopausal symptoms revealed 8 cases of ovarian cancer. This risk was 2 to 3 times greater than expected. The risk increased with the strength of premarin tablet usually taken, but not with the duration of use or total dose ingested. The excess risk of ovarian cancer in this group occurred primarily among 21 women who had also used stilboestrol (diethylstilbestrol). The results of this small trial are consistent with the increasing incidence of ovarian cancer in post-menopausal women in the U.S.A., and with the occurrence of stilboestrol-induced ovarian neoplasms in dogs.

Cocarcinogenesis↗

PubMedDate not supplied

Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol.

Gamma-interferon (IFN-gamma) plays an important role in the maintenance of immune homeostasis by regulating the functions of all key cells of the immune system. Pathologically, IFN-gamma has been implicated in several autoimmune diseases. Since estrogens affect autoimmunity, we investigated whether immunomodulatory estrogenic hormones affects IFN-gamma. Concanavalin-A-stimulated splenic lymphocytes from orchiectomized or ovariectomized C57BL/6 mice exposed to estrogen for 3-5 months secreted higher levels of IFN-gamma protein compared to controls. This increase is, in part, due to increased levels of IFN-gamma mRNA. Kinetic studies suggested that splenic lymphocytes from estrogen-treated gonadectomized mice had increased IFN-gamma mRNA and protein as early as 6-12 h of culture. Estrogen also increased the expression of co-stimulatory CD80 (B7-1) molecules on B cells. Since natural estrogen increases IFN-gamma, it became important to test whether diethylstilbestrol (DES, a synthetic estrogen which was given to millions of women) also alters IFN-gamma levels. Our initial investigatory studies show that prenatal mice exposed to DES had a normal ability to secrete IFN-gamma. However, a second exposure of these mice to DES (single dose of 1 microg/g.b.w), as late as 1-1.5 years of age, led to a pronounced increase in the number of IFN-gamma secreting cells and augmented secretion of IFN-gamma. Increased IFN-gamma secretion by splenic lymphocytes from these mice was noted even after stimulation with a submitogenic concentration of anti-CD3 antibodies with or without anti-CD28 antibodies. Cell mixing experiments suggested that the DES-induced increase in IFN-gamma secretion is due to hormonal effects on T cells but not on APC. Together our studies show that: (1) estrogens upregulate IFN-gamma secretion, a vital immunoregulatory cytokine, and (2) inappropriate exposure of developing fetus to DES may permanently alter the "cytokine programming" of lymphocytes.

Animals↗