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PubMed1981

Possible relationship between in utero diethylstilbestrol exposure and male fertility.

Seventeen men who were exposed in utero to diethylstilbestrol (DES), 12 non-DES-exposed volunteers, and 11 fertile control subjects were evaluated by physical examination, seminal fluid analysis, and sperm penetration assay (SPA). Fourteen of the 17 male subjects exposed to DES in utero and two of the 12 non-DES-exposed volunteers had SPAs of less than 14% and qualified as infertile by the criteria of this test. All 11 fertile control subjects had demonstrated SPA values in the fertile range. Thirteen of the 17 DES-exposed male subjects, four of the 12 non-DES-exposed volunteers, and four of the 11 fertile control subjects demonstrated at least one abnormality of the reproductive organs.

Adolescent↗
PubMed1981

Pregnancy outcome in women exposed to diethylstilbestrol in utero.

The presence of anomalies in vagina, cervix, and uterine body of women exposed to diethylstilbestrol in utero has provoked interest and concern regarding the reproductive potential of these women. To expand and to evaluate better better the current knowledge in this matter, the outcomes of the pregnancies of exposed women registered in the Stilbestrol Clinic at the Stanford University Medical Center were examined. The results were combined with the published results of similar examinations of other institutions and a summation of all available data is presented. Although it is evident that the majority (79%) of exposed women who have become pregnant and not regularly sought abortion have obtained at least one living infant, the incidence of spontaneous abortion and preterm delivery has consistently been found to be greater in exposed women than in unexposed control women. One of every 30 pregnancies reported in exposed patients has been ectopically located. Additionally, there is suggestive evidence that exposed women with teratologic changes have a higher incidence of pregnancy loss than those without such changes. However, few of these observations can boast statistical validity and statistical validation of the same observation by separate investigators has not been obtained. Moreover, none of th teratologic changes in exposed patients has been seen to preclude normal pregnancy and term delivery.

Abortion, Induced↗
PubMed1982

Effects of prenatal exposure of mice to "low-dose" diethylstilbestrol and the development of adenomyosis associated with evidence of hyperprolactinemia.

The developing genital tract of the fetal mouse was exposed to diethylstilbestrol (DES) and the induction of noncyclic ovarian function in adult life was circumvented. Female mice of two inbred strains, BALB/c and C3H, were mated with BALB/c male mice and on the seventh day of pregnancy were fed a diet containing 0.2 micrograms of DES/gm continuously until the morning after delivery of the young. This regimen did not interfere appreciably with continuance of pregnancy, and offspring of normal body weight were delivered. When the mice reached maturity, the fertility and fecundity of the cycling exposed female mice were, however, reduced significantly. Virgin exposed BALB/c female mice, observed until 18 months of age, developed neoplasms with the same low frequency normally encountered in this strain, while the exposed hybrids developed mammary carcinomas almost twice as often as did an unexposed population. In addition, two benign lesions of the genital tract occurred frequently in the exposed hybrid female mice. The most extensive of these resembled adenomyosis as seen in the female human in that foci of nonneoplastic endometrium penetrated the muscular layers of the uterus, often forming small, fluid-filled blebs evaginating the serosal surface. This lesion was reproduced by grafting day-old female mice with a single ectopic hypophysis, indicating that chronic hyperprolactinemia was a major endocrine factor in its genesis. The second was an enlargement of the cervix with extensive mucoid alterations within the muscularis, a lesion that could be produced by the continuous estrogenization of adult animals. Both lesions occurred to a much lesser extent in BALB/c female mice, and neither was felt to contribute to the reduced fecundity noted in DES-exposed female mice.

Animals↗
PubMed1982

Hirsutism and menstrual patterns in women exposed to diethylstilbestrol in utero.

Hirsutism and menstrual patterns were evaluated in 32 female patients with documented diethylstilbestrol (DES) exposure in utero. Nine nonhirsute regularly menstruating and nine consecutive hirsute oligomenorrheic women with no known DES exposure served as controls. Hormone measurements included follicle-stimulating hormone, luteinizing hormone, prolactin, cortisol, testosterone, androstenedione, dehydroepiandrosterone, sex hormone-binding globulin, and estradiol. Hirsutism was present in 72% and irregular menses occurred in 50% of DES-exposed patients. The mean age of the DES-exposed group was 26.8 +/- 0.7 years (mean +/- SEM). The mean age of mildly hirsute DES-exposed patients (24.7 +/- 1.4 years) was significantly lower (p less than 0.05) than that of severely hirsute DES-exposed patients (28.8 +/- 1.1 years). Mean testosterone, androstenedione, sex hormone-binding globulin, testosterone/sex hormone-binding severely hirsute DES-exposed group but higher than in nonhirsute control subjects. Mean testosterone, androstenedione, sex hormone-binding globulin, testosterone/sex hormone-binding globulin, and luteinizing hormone levels in hirsute DES-exposed patients were similar to those in hirsute control subjects but significantly higher than those in nonhirsute control subjects. Mean DHA levels as well as the clitoral indices were comparable in all groups. Our data suggest that DES exposure in utero may result in hypothalamic-pituitary-ovarian dysfunction.

Androstenedione↗
PubMed1983

Maturation of vaginal and cervical epithelium in women exposed in utero to diethylstilbestrol (DESAD Project).

A total of 452 women with documented exposure in utero to diethylstilbestrol (DES) with epithelial findings present at the time of their initial examination have been evaluated prospectively to determine whether these findings changed over a period of 3 years. The examinations were all performed according to a strict protocol. Findings present at the time of the third annual examination were verified at a fourth examination. A verified decrease in the extent of epithelial findings occurred in 29.2% of these women and a verified increase in 6.6%; 53.1% had no change in the extent of epithelial findings, and 11.1% had a change that could not be verified at the time of the fourth visit. Analysis of many variables failed to identify a strong association between any variable and a decrease in the extent of the findings. It appears that the most important factor in the occurrence of changes in DES-associated findings is the passage of time.

Adolescent↗
PubMed1984

Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol-exposed progeny.

Previous studies have suggested that there is an association between genital tract abnormalities and pregnancy outcome in women exposed to diethylstilbestrol (DES) in utero. In a collaborative study, 676 DES-exposed women had hysterosalpingographic examinations, and the findings were related to the outcome of pregnancy in 327 of these women. The findings revealed that (1) there is a considerable variation of frequency of different types of upper genital tract anomalies in women from different sources and with different motivations for enrollment in the study, (2) the presence of structural cervical changes and vaginal epithelial changes are markers for the likelihood of abnormalities in the uterine fundus, (3) women with upper genital tract abnormalities have increased odds for poor pregnancy outcome as compared to women with normal hysterosalpingographic findings, and (4) although some abnormalities were most often or consistently associated with poor pregnancy outcome, no specific changes could be related to specific types of pregnancy outcomes.

Abortion, Spontaneous↗
PubMed1986

Upper genital tract changes and infertility in diethylstilbestrol-exposed women.

A possible relationship of upper genital tract abnormalities in the diethylstilbestrol-exposed woman and infertility was studied. Six hundred thirty-two women had roentgenography performed. Three hundred sixty-seven of these women were not using contraception and were actively trying to become pregnant. One hundred thirty-four (36%) of these women reported difficulties conceiving for a period of 1 or more years. Seventy-three percent of these women had abnormal hysterosalpingograms. The frequency of abnormal x-ray films in the women who did conceive within 1 year was essentially the same (74%). Furthermore, a similar number of women with normal x-ray films (37%) had difficulty conceiving as did women with abnormal x-ray films (36%). When specific hysterosalpingographic abnormalities were related to the presence or absence of infertility, it was observed that the presence of a constriction of the upper uterine cavity resulted in a 2.26-times greater likelihood that a woman would not be able to conceive. If a T-shaped uterus was found in association with constriction of the upper uterine cavity, the odds ratio for inability to conceive was found to be 2.63.

Abnormalities, Drug-Induced↗
PubMed1981

Influence of magnesium in the homogenization medium on the state of a divalent cation-stimulated, diethylstilbestrol-sensitive adenylnucleotidyl phosphatase activity from pea stem microsomal preparations.

The amount of divalent cation-activated, diethylstilbestrol-sensitive adenylnucleotidyl phosphatase activity recovered in the 'microsomes' (13000-80000 X g sediment) from pea stem tissue is strongly influenced by concentration of Mg2+ in the homogenization medium. The absence of Mg2+ during homogenization results in a marked decrease of the activity found in the microsomal fraction, compensated by its increase in the soluble fraction. Part of the solubilized activity becomes sedimentable at 80000 X g upon addition of 5-10 mM Mg2+ (or Mn2+, Ca2+, Zn2+) to the supernatant. This sediment shows a very high specific activity, and can be re-solubilized by treatment with either EDTA or 0.3 M monovalent salts, or deoxycholate. When the supernatant containing the solubilized activity is incubated together with low-adenylnucleotidyl phosphatase microsomes and with 10 mM MgCl2 the activity recovered in the sediment is much larger than the sum of the activity of the microsomes plus that of the sediment obtained by incubating the same supernatant with Mg2+. Microsomes prepared with Mg2+ in the homogenization medium do not show this effect. The supernatant/microsomes saturation curves as well as a change of the temperature coefficient of the activity following combination of the soluble preparation with the microsomal particles suggest an at least partial reconstitution of the original enzyme-membrane structure.

Adenosine Triphosphatases↗
PubMed1983

Diethylstilbestrol (DES) quinone: a reactive intermediate in DES metabolism.

The quinone of E-diethylstilbestrol (DES), a postulated metabolic intermediate derived from DES, has been synthesized by oxidation of DES in chloroform using silver oxide. The reaction product was structurally characterized by infrared, ultraviolet, nuclear magnetic resonance, and mass spectrometry. The product of oxidation of DES by hydrogen peroxide, catalyzed by horseradish peroxidase and also by rat uterine peroxidase, was shown to be identical with synthetic DES quinone based on identical u.v. spectra and on identical decomposition products. DES quinone was stable only in non-protic solvents such as chloroform. In acids, bases or protic solvents, DES quinone rearranged to Z,Z-dienestrol (beta-DIES). The half-life of DES quinone in water was approximately 40 min; in methanol it was approximately 70 min. Bacterial mutagenicity (Ames) tests did not indicate that DES quinone had mutagenic or genotoxic activity. However, DES quinone was found to bind to calf thymus DNA without any enzyme mediation at levels significantly above the binding of DES under the same conditions. Based on the binding of DES quinone to DNA, this intermediate must be considered as a possible carcinogenic metabolite of DES.

Animals↗
PubMed1985

DNA clastogenic activity of diethylstilbestrol.

Incubation of human leukocytes with the synthetic estrogen and known human carcinogen, diethylstilbestrol (DES), for 40 min caused extensive DNA strand breakage (clastogenesis), as measured by a fluorometric assay. The level of DNA clastogenesis was dose dependent above an apparent threshold of 10 microM. Clastogenesis was increased by addition of cysteamine, a reducing agent and hydroxyl radical scavenger, and was blocked by low concentrations of plasma. DES epoxide, a weakly estrogenic derivative, was about one-tenth as potent as a DNA clastogen. Unexpected and paradoxical findings were observed when cells were treated with DES in the presence of a hydrogen peroxide-generating system plus a peroxidase. At the subthreshold concentration of 10 microM DES, the oxidizing system increased DNA clastogenicity, yet at 30 microM DES the oxidizing system decreased clastogenicity. The addition of superoxide dismutase to the oxidizing system increased clastogenicity at both concentrations of DES. DNA damage was largely blocked by arsenite, N-ethylmaleimide, iodoacetamide and bromophenacyl bromide. These experiments provide further indication of the complex nature of reactions involving DES which can lead to DNA damage and which may be relevant to DES-induced carcinogenesis.

Adult↗
PubMed1985

Induction of DNA single- and double-strand breaks by diethylstilbestrol in murine L5178Y lymphoblasts in vitro.

The mechanism of action of the synthetic estrogen diethylstilbestrol (DES) was investigated in murine L5178Y lymphoblasts. The dose-survival curve of cells treated with DES in serum-free medium for 1 hr was characterized by a prominent shoulder followed by a simple exponential decline; the Do, the dose of DES reducing cell survival to 1/e, was 1.52 nmoles/ml. DNA single-strand breaks, as measured by the alkaline elution method, were observed in DES-treated cells, and these followed a dose-response relationship after an apparent threshold of 10 microM DES was exceeded. Protein-associated strand breaks, which represent the increment in single-strand breaks that occurs by exposing drug-treated cells to proteinase K, were also noted. DNA double-strand breaks as measured by filter elution technology at pH 9.6 were observed and increased markedly to reach a level of approximately 9000 rad equivalents at a DES concentration of 20 microM. The measured ratio (mean +/- S.E.) of single- to double-strand breaks induced by DES in L5178Y limphoblasts was 0.09 +/- 0.035. A comparison of the ratio of single- to double-strand breaks induced by DES to that observed following radiation suggested that all of the single-strand breaks produced by DES could be attributed to double-strand breaks. The close correspondence of the dose-response curve for cytocidal activity of DES with that obtained for induction of DNA double-strand breaks suggested that such breaks may play an important role in the mechanism of cell kill by DES.

Animals↗
PubMed1986

Metabolism and irreversible binding of diethylstilbestrol in the kidney of the Syrian golden hamster.

Oxidative metabolism of [3H]diethylstilbestrol (DES) and the irreversible binding of reactive [3H]DES metabolites to the macromolecules in kidney slices of Syrian golden hamster were investigated. Non-extractable binding of [3H]DES to kidney macromolecules was observed after incubating hamster kidney slices under aerobic conditions (95% O2/5% CO2), but not under anaerobic conditions (100% nitrogen + 2 mM KCN). A number of oxidative metabolites of [3H]DES were detected in the incubation medium of kidney slices incubated under aerobic, but not anaerobic, conditions. The amount of radiolabeled macromolecules formed in male cortical slices under aerobic conditions increased with time of incubation. At a medium concentration of 50 nM [3H]DES, 0.08 pmole [3H]DES equiv./mg dry weight at 30 min and 0.19 pmole [3H]DES equiv./mg dry weight at 120 min were observed. The amount of irreversible [3H]DES-macromolecular complexes also increased with the concentration of [3H]DES in the incubation medium: 1.59 pmole [3H]DES equiv./mg dry weight was formed with 0.5 microM [3H]DES and 21.89 pmole [3H]DES equiv./mg dry weight was formed with 10 microM [3H]DES. Non-extractable [3H]DES binding was detected in all the subcellular fractions of hamster kidney with the highest amount in the microsomal and soluble fractions, followed by the mitochondrial and nuclear fractions. The macromolecular-[3H]DES complexes were solubilized by proteases but not nucleases, suggesting that [3H]DES irreversible binding is principally to the proteins and not the nucleic acids. The cortex as compared with the medulla of the male hamster kidney displayed a 5-fold greater capacity to irreversibly bind [3H]DES metabolites. The male hamster renal cortex showed a 2- to 3-fold greater capacity to form irreversible macromolecular-[3H]DES complexes than the female hamster renal cortex. These data demonstrate that: (1) renal oxidative metabolism of DES results in [3H]DES metabolites binding irreversibly to macromolecules; and (2) the sex and organ site specificity of the [3H]DES-macromolecular binding corresponds with the sex and organ site specificity of renal tumors of the hamster.

Aerobiosis↗
PubMed1986

Comparison of the disposition of diethylstilbestrol and estradiol in the fetal rat. Correlation with teratogenic potency.

The dispositions of radiolabeled diethylstilbestrol (DES) and estradiol (E2) in the fetal rat were compared to determine whether kinetic differences accounted for their differences in teratogenic potency. 14C (from DES) was concentrated in fetal tissues relative to plasma, whereas 3H (from E2) was largely retained protein-bound in fetal plasma. Both compounds were rapidly metabolized in the fetus (and mother) to less or non-estrogenic products. Fetal levels of E2 declined faster than those of DES (E1 was the primary circulating estrogen within 1-3 hr of E2 injection) so that exposure to unchanged DES was of longer duration than to E2. The unchanged compounds were retained longer and at higher concentrations in the target genital tissue compared to other tissues. Although these differences were consistent with the potencies, the concentration of the unchanged estrogen in fetal genital tract was lower after a teratogenic dose of DES than after a threshold teratogenic dose of E2. However, the 3H in fetal plasma and genital tract cytosol at 1 hr after injection of [3H]E2 at 2 ng or 10 micrograms/fetus was found to be highly protein-bound. DES competed poorly for these binding sites. It is suggested that the concentration of E2 which is "free" in the cell (as DES is), rather than the total content, correlates with its teratogenicity. Thus, in the rat, rapid metabolism and extensive protein-binding, both extra- and intracellularly, reduce the teratogenicity of the natural estrogen compared to the synthetic estrogen.

Abnormalities, Drug-Induced↗
PubMed1987

Metabolism of diethylstilbestrol in hamster hepatocytes.

Under certain modulating conditions the liver of the male Syrian golden hamster is a target organ for the carcinogenic effect of the synthetic estrogen diethylstilbestrol (DES). As a basis for mechanistic studies aimed at elucidating the role of metabolic activation in the process of DES-induced neoplasia, the metabolism of 14C-DES was investigated in freshly isolated hamster hepatocytes. These oxidative metabolites of DES, viz. Z,Z-dienestrol,3'-hydroxy-DES and 1-hydroxy-E-DES, were formed in 14.2, 9.1, and 0.3% yield, respectively, when hepatocytes were incubated with 50 nmol DES/mg cellular protein for 60 min. Glucuronides (4.0%) and sulfates (2.8%) of DES and of the oxidative metabolites were also found, and non-extractable binding of radioactivity to cellular protein was observed indicating the formation of reactive intermediates. The capability of hamster hepatocytes to oxidize and conjugate DES should allow the investigation of the effects of modulators on the metabolic activation of DES in this cellular system in order to help clarify the mechanisms of DES-induced hepatocarcinogenesis.

Animals↗
PubMed1982

Diethylstilbestrol regulates the number of alpha- and beta-adrenergic binding sites in incubated hypothalamus and amygdala.

Previous work has identified an effect of circulating estrogens on the number of central adrenergic binding sites. We have further characterized this effect by performing the experiments in vitro and have taken advantage of a well-described hypothalamic preparation in which diethylstilbestrol (DES), is known to elevate cAMP levels through a pathway which involves adrenoreceptors. We show that DES induces a reciprocal change in the numbers of alpha- and beta-adrenergic binding sites in incubated hypothalami obtained from intact immature female rats as well as from ovariectomized adult rats. The alpha-adrenergic binding sites are reduced by 25-30% whereas the beta-adrenergic sites are increased by 60-100%. The effect is maximal at 3 h in vitro (20 microM DES) and largely reversible following a 2 h wash in the absence of DES. Using the change in beta-adrenergic binding sites as a probe, we were further able to show that estradiol (100 microM) and 2-hydroxyestradiol (50 microM) had no effect. Further, the effect of DES was not blocked by the anti-estrogens clomiphene or tamoxifen. Since DES is able to elevate beta-adrenergic binding sites in hypothalamus and amygdala (brain areas known to contain high levels of estrogen receptors) but has no effect in cerebellum, we conclude that we have observed an effect of DES not shared by estradiol but which may be confined to estrogen target areas of the brain.

Amygdala↗
PubMed1984

Pre- and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats.

The volume of the sexually dimorphic nucleus in the preoptic area (SDN-POA) of the rat brain is several fold larger in males than in females. When female rats were treated pre- and postnatally with testosterone propionate (TP) or with diethylstilbestrol (DES) they became anovulatory and their SDN-POA developed equivalent in size to that of normal males. Identical treatment of male rats resulted in deficient testicular development, but had no influence on SDN-POA volume. The results indicate that the gross morphological sex difference in SDN-POA volume can exclusively be controlled by the hormonal environment during the critical period of sexual brain differentiation, and that non-steroidal estrogens are just as effective as convertible androgens in stimulating SDN-POA differentiation.

Animals↗