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PubMed1981

Genital abnormalities and abnormal semen analyses in male patients exposed to diethylstilbestrol in utero.

Urologic examination of 48 male patients exposed in utero to diethylstilbestrol showed genital abnormalities in 29. Only 33 per cent of the patients studied had normal semen analyses by Eliasson scoring. Genital abnormalities demonstrated included varicoceles, epididymal cysts, hypoplastic testes and undescended testes among others. None of the patients had elevations of alpha-fetoprotein or beta-subunit human chorionic gonadotropin. The high incidence of the aforementioned abnormalities suggests that all male patients exposed to diethylstilbestrol should undergo urologic examination and semen analysis. Additionally, a history of diethylstilbestrol exposure should be sought in all patients with apparent idiopathic infertility.

Abnormalities, Drug-Induced↗

PubMed1978

Metabolism of diethylstilbestrol: identification of a catechol derived from dienestrol.

The enzymatic oxidation of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene (diethylstilbestrol) by either mushroom tyrosinase or rat liver microsomes in the presence of NADPH and air yields a catechol. Upon further oxidation of both compounds with periodate and condensation of the resulting o-quinones with o-phenylenediamine, phenazines are produced. The phenazines derived from the products of both the plant and animal enzyme systems are identical to the product obtained by oxidation of diethylstilbestrol with potassium nitrosodisulfonate and condensation of the o-quinone produced with o-phenylenediamine. High and low resolution mass spectra of the phenazine are consistent with its derivation from a catechol having two fewer hydrogens than diethylstilbestrol.

Animals↗

PubMed1986

Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate.

Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono- or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES greater than DES-MP much greater than DES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.

Animals↗

PubMed1994

Comparison of DNA reactivity of the polyphenylethylene hormonal agents diethylstilbestrol, tamoxifen and toremifene in rat and hamster liver.

The polyphenylethylene estrogenic drug diethylstilbestrol and a structural analogue tamoxifen have been found to be hepatocarcinogenic in female rats, whereas another analogue, toremifene, did not induce liver tumors. The 32P post-labelling technique for detection of DNA adducts was used to investigate the DNA reactivity of these three hormonal agents in the livers of female Sprague-Dawley rats and Syrian hamsters. Adducts were quantified using a radioanalytic imaging system in comparison with the standard Cerenkov assay. With administration of the chemicals at several doses by daily gavage to rats for 10 days and to hamsters for 7 days, tamoxifen was found to produce five adducts in rat liver and six adducts in hamster liver. The amounts of adducts were dose related from 10 to 90 mumol/kg per day in rats and from 17 to 160 mumol/kg per day in hamsters. The two methods of quantification yielded comparable results. Under these conditions, neither toremifene nor diethylstilbestrol produced adducts in rats and diethylstilbestrol produced none in hamsters. We conclude that tamoxifen is highly DNA reactive in the species studied and that this is likely to be involved in its strong carcinogenicity in rat liver.

Animals↗

PubMed1995

Onset of menopause in women exposed to diethylstilbestrol in utero.

OBJECTIVES: As part of a larger health survey, we sought to determine whether prenatal exposure to diethylstilbestrol is associated with onset of early menopause or menopausal symptoms. STUDY DESIGN: Diagnosis of premature ovarian failure and symptoms of menopause were determined in a telephone interview with 542 women whose mothers participated in a randomized clinical trial of the use of diethylstilbestrol in pregnancy in the early 1950s. These women were aged 37 to 39 at the time of the interview. Medical records were obtained to confirm diagnosis of premature ovarian failure. RESULTS: The prevalence of menopausal symptoms (specifically hot flashes and night sweats) did not differ for exposed and unexposed women. One exposed woman and no unexposed women had a medically confirmed diagnosis of premature ovarian failure. CONCLUSIONS: Prenatal diethylstilbestrol exposure was not related to diagnosis or symptoms of menopause in this study. Further follow-up will be necessary to determine if a difference in age at menopause emerges as these women become older.

Adult↗

PubMed1995

Age at menarche among diethylstilbestrol granddaughters.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women's daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother's prenatal diethylstilbestrol exposure.

Adolescent↗

PubMed1995

Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07.

PURPOSE: RTOG 83-07 is a Phase II randomized protocol designed to compare the efficacy and toxicity of Megestrol vs. Diethylstilbestrol (DES) used as cytoreductive agents prior to and during radiotherapy. The end points of this study include tumor clearance rate, effect on serum testosterone, loco-regional control, disease-free interval, and survival. METHODS AND MATERIALS: Eligible patients were those with histologically confirmed locally advanced adenocarcinoma, clinical Stage B2 (T2B) and C (T3) without regional lymph node involvement, or with lymph node involvement limited to the pelvis. Patients were stratified by clinical stage, histological grade, and nodal status, and were randomized to receive either Megestrol 40 mg three times per day by mouth, or Diethylstilbestrol 1 mg three times per day by mouth. The drugs were started 2 months prior to initiation of radiotherapy and were continued throughout the radiotherapy course. Radiotherapy consisted of 44-46 Gy, 1.8-2 Gy per day to the regional lymphatics, followed by a boost to the prostate consisting of 20-25 Gy, 1.8-2 Gy per day, to a total of 65-70 Gy. Serum testosterone levels were recorded throughout the treatment course. Tumor response was assessed clinically and radiographically (CT scan). From March 1983 through June 1986 a total of 203 patients were accessioned to the study; 198 were analyzable. RESULTS: Correlation of the incidence of drug-related toxicity and treatment arm assignment revealed a significantly higher incidence of complications in the Diethylstilbestrol (DES) arm. The most prominent were the differences in the incidence of gynecomastia (55% vs. 7%) and fluid retention (21% vs. 6%). The incidence of thromboembolic phenomena was comparable (8% vs. 5% in the Megestrol arm). Patients on the DES arm demonstrated a significantly greater median decrease in testosterone level. Correlation of the treatment arm assignment and the rate of tumor regression and the incidence of complete response revealed no significant difference between the arms. At 7 years, 16% of patients on the Megace arm and 21% of patients on the DES arm manifested evidence of local failure. CONCLUSIONS: The results of the study indicate comparable efficacy (using tumor clearance as an end point) of DES and Megestrol. Although DES appears more effective in suppressing testosterone, it is also associated with a higher incidence of drug-related toxicity.

Adenocarcinoma↗

PubMed1986

Cardiovascular side effects of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate used for the treatment of advanced prostatic cancer: results from European Organization for Research on Treatment of Cancer trials 30761 and 30762.

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

Aged↗

PubMed1984

Morbilliform skin eruption owing to diethylstilbestrol.

We describe an unusual case of morbilliform skin eruption caused by diethylstilbestrol in a patient with stage D prostatic cancer. A widespread erythematous maculopapular rash and urticaria appeared with repeated challenges of diethylstilbestrol and resolved with drug withdrawal. In addition, the literature on various types of dermatitis medicamentosa in male patients with prostatic cancer treated with diethylstilbestrol is reviewed.

Aged↗

PubMed1980

Effect of diethylstilbestrol on plasma testosterone levels during 24 hours: study comparing doses of 1 and 5 mg. daily, and 1 mg. 3 times daily.

A study was done on 30 patients with advanced adenocarcinoma of the prostate treated with diethylstilbestrol. Three groups of patients were given daily doses of 1, 5, and 1 times 3 mg. diethylstilbestrol, respectively. The study was confined to the effects of treatment on the levels of plasma testosterone by taking hormonal specimens every 4 hours for 24 hours. The results showed little difference of plasma testosterone among the groups under study and a statistical analysis showed no significant differences. Therefore, our study showed no appreciable advantage in the dosage spread over the day, compared to commonly used doses of 1 or 5 mg. diethylstilbestrol given in a single dosage.

Adenocarcinoma↗

PubMed2000

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring.

OBJECTIVE: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. METHODS: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. RESULTS: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64. 1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). CONCLUSION: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

Abortion, Spontaneous↗

PubMed1984

The structure of 4',4''-diethylstilbestrol (DES) quinone.

The structure of 4',4''-diethylstilbestrol quinone (DES quinone), a short-lived metabolic intermediate of the synthetic estrogen E-diethylstilbestrol (DES), was investigated by 13C- and 1H-nmr. Selected homonuclear decoupling experiments were carried out to identify the carbons and protons with which resonances were associated. The 1H-nmr spectrum of DES quinone remained unchanged in the temperature range from 25 degrees C to 65 degrees C. The spectral results suggested the structure of DES quinone to be planar or time-averaged planar with the exception of the freely rotating ethyl groups. The conformation of this intermediate was found to be transoid without any indication of conversion through a cisoid conformation. The similarity of the 1H-nmr spectrum of 3',3'',-5',5''-tetrafluoro-4',4''-diethylstilbestrol quinone (TF-DES quinone) and that of the non-fluorinated parent suggested a high degree of structural similarity. The planar structures of the quinone intermediates differed from those of DES or Z,Z-dienestrol which were not coplanar with respect to the aromatic ring systems.

Chemical Phenomena↗

PubMed2006

Mortality in women given diethylstilbestrol during pregnancy.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Adult↗

PubMed2004

Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity.

The estrogen-related receptor (ERR) gamma behaves as a constitutive activator of transcription. Although no natural ligand is known, ERRgamma is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERRgamma ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERRgamma results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the "activation helix" (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ERalpha LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERRgamma does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERRgamma and ERalpha reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERRgamma relative to ERalpha. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERRgamma and reveal structural differences with ERs that explain why ERRgamma does not bind estradiol or raloxifene and will help to design new selective antagonists.

Animals↗

PubMed1981

Diethylstilbestrol induces neoplastic transformation without measurable gene mutation at two loci.

The frequency with which diethylstilbestrol induces neoplastic transformation and somatic mutation was measured concomitantly in Syrian hamster embryo cells. While diethylstilbestrol was as active as benzo[a]pyrene in inducing transformation, it failed to induce mutations at two conventionally studied loci. These results suggest that diethylstilbestrol may transform cells in the absence of gene mutations.

Animals↗

PubMed2001

Vaginal adenosis in a non-diethylstilbestrol-exposed 6-year-old patient.

Vaginal adenosis is rare, and it is defined as the presence of metaplastic cervical or endometrial epithelium within the vaginal wall. It is associated with in utero exposition to diethylstilbestrol and a high risk of vaginal carcinomas. A case of vaginal adenosis arising in a non-diethylstilbestrol-exposed 6-year-old patient is presented. Few cases have been described in children and adolescents, and since the withdrawal of diethylstilbestrol from the market, this condition is rarely described in the medical literature. However, it should be considered as a possible diagnosis in girls with persistent vaginal discharge.

Biopsy↗

PubMed2006

Effects of diethylstilbestrol and ethinylestradiol on gene transcription of very low-density apolipoprotein II in the liver of Japanese quail, Coturnix japonica.

Very low-density apolipoprotein II (apoVLDL) is one of the constituents of yolk in avian eggs. The expression of the apoVLDL gene is highly specific to the liver in mature female birds during the egg-laying period but is stimulated by exogenous estrogens in immature male birds. In the present study, we compared the effects of two estrogenic compounds, diethylstilbestrol and ethinylestradiol, on the expression of apoVLDL mRNA in the liver of Japanese quail (Coturnix japonica). Three-week-old, immature male quail were treated with a single intraperitoneal injection of the estrogenic compounds, and the level of apoVLDL mRNA in the liver was measured by gene-specific real-time polymerase chain reaction. Diethylstilbestrol and ethinylestradiol had a similar effect on the level of mRNA, increasing it in a dose-dependent manner. Next, the levels of apoVLDL mRNA in the liver of male embryos, which were developed in fertile eggs laid by quail injected with the estrogenic compounds during yolk formation, were measured. Maternal exposure to ethinylestradiol caused an increase in the mRNA in embryos, whereas exposure to diethylstilbestrol had no effect. These results point out the importance of the route of administration to the evaluation of the estrogenic effects of endocrine disruptors in oviparous species.

Animals↗

PubMed1989

Abnormalities of the uterus and cervix after diethylstilbestrol exposure: correlation of findings on MR and hysterosalpingography.

We determined the value of MR for detecting abnormalities of the uterus caused by in utero exposure to diethylstilbestrol in patients in whom such abnormalities were evident on hysterosalpingography. Of 200 women with a history of diethylstilbestrol exposure in utero, 12 had undergone hysterosalpingography as part of an infertility workup. Five of these volunteered to undergo MR imaging of the pelvis. Hysterosalpingography showed abnormalities in all five patients. Abnormalities included hypoplasia of the uterine cavity (3/5), a T-shaped uterine cavity (3/5), constrictions of the uterine cavity (3/5), irregular margins of the uterine cavity (2/5), bilateral hydrosalpinges (2/5), and a diverticulum of a fallopian tube (1/5). MR images showed abnormalities in all five patients. These included hypoplasia of the uterine cavity, uterine corpus, and cervix (3/5); a T-shaped uterine cavity (3/5); constrictions of the uterine cavity (3/5); and bilateral hydrosalpinges (2/5). There was an excellent correlation between the findings on MR images and those on hysterosalpingograms. A thick junctional zone was identified on MR as the cause of constrictions of the uterine cavity seen on hysterosalpingography. MR failed to show the irregular margins of the uterine cavity in two of five cases and a diverticulum of the fallopian tube. We conclude that MR can be used to detect hypoplasia and other congenital abnormalities of the uterus in women with a history of diethylstilbestrol exposure in utero.

Adult↗