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PubMed1997

The effect of somatostatin analog octreotide on diethylstilbestrol-induced prolactin secretion, cell proliferation and vascular changes in the rat anterior pituitary gland.

The effects of diethylstilbestrol (DES) and of long-acting somatostatin analog, octreotide (SMS) on the rat anterior pituitary microvasculature have been studied by means of computer-assisted image analysis. Additionally, the effects of DES and SMS on prolactin secretion and anterior pituitary cell proliferation have been studied, as well. The vascularization was visualized using Selye's method modified by Poely et al. (1964). The prolactin serum levels were estimated by radio-immunoassay. The proliferation indices were assessed using bromodeoxyuridine incorporation assay. As expected, it was found that DES sharply increased serum prolactin levels and enhanced cell proliferation in the anterior pituitary gland. DES also induced changes in parameters of vascularization. Simultaneous treatment of rats with SMS inhibited the DES-induced elevation of prolactin levels and pituitary cell proliferation. It also suppressed some but not all DES-induced changes in the anterior pituitary vascularization. These data suggest that the angio-inhibitory activity of SMS might be involved in its anti-tumor action on pituitary adenomas, but not as a sole or principal mechanism.

Animals↗

PubMed1997

Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus.

Alteration of DNA demethylation in five CpG sites (-547, -533, -475, -464, and -454) immediately upstream from the estrogen response element of lactoferrin promoter was determined in the uteri of immature (17-day-old) and mature (21- and 30-day-old) mice treated neonatally with DES. Only the CpG/-464 was found to be abnormally demethylated by diethylstilbestrol (DES) treatment in the mature uteri. This abnormal demethylation occurred in specific response to DES in neonatal mice, because DES injected into the 30-day-old mature mice did not demethylate CpG/-464. This site, however, remained methylated in the neonatally DES-treated/ovariectomized mice, indicating that this DES-elicited demethylation is under hormonal control. Thus, neonatal DES treatment appeared to imprint an abnormal, site-specific demethylation of CpG/-464, which requires ovarian hormones to occur in adult mice. Moreover, the demethylation was maintained in uterine tumors of the neonatally DES-treated mice. This mode of demethylation is reminiscent of uterine tumor formation, which also depends on both neonatal DES exposure and ovarian hormone stimulation in adulthood. Thus, neonatal DES treatment may induce tumor formation as well as demethylation through a common cellular process.

Age Factors↗

PubMed1976

Gas-liquid chromatographic determination of diethylstilbestrol at low levels in mixed feeds.

A gas-liquid chromatographic method for the determination of diethylstilbestrol (DES) at 2 ppb in mixed feeds and ingredients is presented. The DES is extracted into ethanol, the solvent is evaporated, and the residue is redissolved in chloroform. The extract is purified by washing the chloroform solution with carbonate buffer and transferring the DES to sodium hydroxide. The sodium hydroxide is washed with chloroform, the pH is adjusted to 10.3, and the DES is transferred to chloroform. The extract is derivatized with hepatafluorobutyric anhydride, chromatographed on an SE-30 glass column, and measured with a 3H electron capture detector. The method has been used for routine testing of a wide variety of feeds and ingredients.

Animal Feed↗

PubMed1997

[Recurrence of cancer of the prostate after initial treatment with diethylstilbestrol (DES) in a homogeneous series of 175 cases].

The study of a homogeneous series of 215 cases of prostatic cancer, 175 of which received first-line treatment with diethylstilbestrol (DES) clearly demonstrated that: 1. practically all well differentiated prostatic cancers, regardless of their stage, responded remarkably well to first-line treatment with sufficient doses of DES, as, when correctly monitored, practically none of these cancers escaped and early stages of escape can be salvaged. 2. true escape occurs all the earlier and evolves all the more rapidly for advanced, poorly differentiated cancers, but this is not constant. 3. to our knowledge, confirmed true metastatic escape to effective doses of DES cannot be salvaged by another treatment, while DES has been successfully used as salvage therapy in several cases of escape to LHRH agonists. 4. the thromboembolic risks must be thoroughly evaluated and prevented by associated anticoagulant treatment. They do not constitute a formal contraindication to treatment when it is closely monitored. However, the best treatment for these cases, when accepted by the patient, appears to be a combination of castration with a daily dose of 1 to 2 mg of DES. 5. The low cost of this treatment must also be taken into account in the assessment of this treatment modality.

Age Factors↗

PubMed1998

[Female fertility prognosis and diethylstilbestrol. Personal data and review of the literature].

Diethylstilbestrol (DES) exposure in utero in females is a cause of clear-cell adenocarcinoma of the cervix and of several anatomical and functional disorders of the genital tract. DES exposure must be evoked whenever counselling women for reproductive disorders. In France around 80,000 women have had in utero DES exposure. The cases of 4 young women who consulted our Reproduction Center for reproductive disorders illustrate the usual difficulties faced by these patients. In spite of their difficult past reproductive history (uterine malformations, repeated miscarriages, ectopic pregnancies) and low fertility rate, all four women conceived successfully, either after spontaneous or induced ovulation. We stress the need for adapted psychological and medical care which can lead to successful childbearing in the vast majority of these high-risk patients.

Adult↗

PubMed1998

[Effect of prenatal treatment with diethylstilbestrol on 1,2-dimethylhydrazine-induced carcinogenesis in male CBA mice].

Female CBA mice were injected 1 mg/kg diethylstilbestrol (DES) on day 17 of gestation. Their male progeny received 15 weekly injections of 1,2-dimethylhydrazine (DMH) starting from the age of 2 months. Prenatal treatment with DES was followed by a significant acceleration and higher frequency of DMH-induced renal adenomas and renal capsule sarcomas in males. Tumor-induction was significantly enhanced by androgen effect. This was matched by a higher frequency of induced tumors of the large bowel. The increased frequency of androgen-dependent renal malignancies, served as indirect evidence of hyperandrogenization being stimulated in CBA male mice by prenatal treatment with DES.

1,2-Dimethylhydrazine↗

PubMed1976

Urogenital tract abnormalities in sons of women treated with diethylstilbestrol.

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices. The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).

Abnormalities, Drug-Induced↗

PubMed1976

Cytology of 575 young women with prenatal exposure to diethylstilbestrol.

The vaginal and cervical cellular changes encountered in 575 postpubertal females exposed prenatally to diethylstilbestrol (DES) were compared with those of an unexposed population with particular reference to the role of cytology in the detection of vaginal adenosis and cervical ectropion (erosion). Several methods of obtaining specimens were utilized, the most effcacious of which was scraping of the vagina, especially the fornices, and the portio vaginalis of the cervix. With this technic, columnar cells of the mucinous type and metaplastic squamous cells were observed in 34% of the vaginal scrapes and 54% of the scrapes of the cervical portio. A higher incidence was apparent among those patients in whom iodine staining of the vaginal mucosa was abnormal or vaginal adenosis was proven by biopsy. Moderate to severe dysplasia of the squamous cells or atypical glandular cells were found in 1% of the exposed subjects. This study indicates that the presence of mucinous columnar or metaplastic squamous cells in vaginal scrapes is suggestive of vaginal adenosis but that vaginal cytology cannot be considered a uniformly reliable screening technic for detecting the presence of this disorder.

Adolescent↗

PubMedDate not supplied

[Uterus and diethylstilbestrol: which examinations, which antecedents for an active management? Which treatments?].

Diethylstilbestrol (DES) was widely prescribed to pregnant women from 1946 to 1977. This resulted in multiple abnormalities of the genital tract. Many studies show an increased incidence of infertility, ectopic pregnancy, spontaneous abortions and premature delivery. For women with certain abnormalities such as a construction of the upper uterine cavity, with or without a T configuration of the uterus, hysteroscopic metroplasty is feasible with good anatomic and functional results.

Carcinogens↗

PubMed1976

Summary of the changes in the human female genital tract as a consequence of maternal diethylstilbestrol therapy.

The current evidence associating maternal ingestion of diethylstilbestrol (DES) with the subsequent appearance of clear-cell adenocarcinoma of the genital tract has been presented. Thus far, these cancers are rare among exposed females. DES, dienestrol, and hexestrol, all nonsteroidal synthetic estrogens, have been implicated. The tumors have appeared primarily in exposed subjects over the age of 14 yr with the median ranging from 18 to 19 yr. Nonneoplastic abnormalities have been observed commonly in the exposed, including vaginal adenosis, cervical erosion (ectropion), and transverse vaginal and cervical ridges. The highest incidence of vaginal adenosis was noted among those whose mothers began DES in early pregnancy, and no cases were observed among those whose mothers began treatment after the 18th wk. Current evidence suggests that these alterations as well as the carcinomas are of mullerian origin.

Adenocarcinoma↗

PubMed1976

Metabolic activation of carcinogenic diethylstilbestrol in rodents and humans.

In vivo biotransformation of diethylstilbestrol (DES) was studied by radio-GLC and GLC-mass spectrometry using both radioactively and deuterium-labeled DES. Among the urinary and biliary metabolites identified in intact Wistar rat and Syrian golden hamsters are dienestrol and hydroxy and methoxy derivatives of dienestrol and DES. The identification of 4'-hydroxypropiophenone as a urinary metabolite of DES in the rat is consistent with the hypothesis that dienestrol is formed via an epoxide-diol pathway. Some of the metabolites imply electrophilic reactivity according to their chemical structure and may represent proximate carcinogens of DES. In humans, dienestrol and hydroxy dienestrol constitute the major urinary DES metabolites in men and were also identified in the urine of a woman. Considerable species differences in DES metabolism between humans and rats were found with regard to the route of excretion and the pattern of urinary metabolites.

Adult↗

PubMed1976

Dose-dependent kinetics of diethylstilbestrol in the rat.

Diethylstilbestrol (DES) acts as a transplacental carcinogen with organotropic properties. The question is raised whether the pharmacokinetics of DES contribute to this effect. [3H] DES was administered to female Wistar rats orally, intravenously, and introperitoneally at doses ranging from 0.025 to 25 mg/kg. Radioactivity associated with erythrocytes and plasma proteins was measured and the pattern of unconjugated metabolites and glucuronides after column and thin-layer chromatography in blood determined. The different routes of administration resulted in different metabolite patterns. After iv injection, unconjugated, unpolar metabolites predomininated; after ip injection, glucuronides of unpolar metabolites; and after oral administration, unconjugated polar metabolites. The different compositions of the glucuronide fractions remained constant with time. The composition of the unconjugated metabolites changed with time after oral administration but not after iv injection. Blood levels of metabolites did not increase proportionally with dose. Overproportional increase was most prominent with the highest dose used. The observed effects are explained with intestinal metabolism and a liver first-pass effect.

Animals↗

PubMed1991

Estrus induction in the bitch using a combination diethylstilbestrol and FSH-P.

The purpose of the study was to induce estrus and ovulation in normal bitches using a combination of diethylstilbestrol (DES) and follicle stimulating hormone of porcine pituitary origin (FSH-P). Thirteen mature mongrel female dogs were divided into two groups, the first group was treated for estrus induction during late anestrus and the second group during mid-anestrus. The dogs were monitored by teasing, vaginal cytology, and hormonal assay during the induced (n=13) and the previous spontaneous estrous cycle (n=9). Six of eight and three of five bitches came into standing estrus in the first and second group, respectively. Of the bitches that came into estrus, three conceived in the first group and one in the second. The average induced litter size was 7.0 versus 7.5 for the colony. Based on vaginal cytology the induced proestrus and estrus lasted 1.7 (0 to 3) and 12.9 (4 to 24) d, respectively, while the spontaneous proestrus and estrus lasted 5.8 (0-17) and 12.8 (9-15) d, respectively. Progesterone profiles were similar between the induced and spontaneous estrous cycles, although the progesterone peak was higher during the spontaneous cycle. The preovulatory luteinizing hormone (LH) surge was observed in only one induced estrous cycle. Modest results were obtained with this therapy. However, the litter sizes were normal and the induced cycles were very similar to the physiologic ones. No side effects were seen with the oral form of DES.

Journal Article↗

PubMed1980

Synthesis and antifertility activity of 3,9-dihydroxy-5,6,6a alpha,6b beta,11,12,12a beta,12b alpha-octahydrodibenzo[a,g]biphenylene, a structural relative of diethylstilbestrol.

The title diphenol, 1a, was synthesized from p,p'-dihydroxy-alpha-truxillic acid and shown to be active as an oral postcoital antifertility agent in rats: ED100 = 100 (micrograms/kg)/day. The oral uterotropic potency was estimated to be 16% of that of diethylstilbestrol (95% confidence limits of potency 8--35%). The structure of the diphenol, 1a, was confirmed by single-crystal X-ray analysis of the dimethyl ether.

Animals↗

PubMed1999

Not just a cervical ectropion. Three case reports of diethylstilbestrol (DES) exposed women presenting with vaginal discharge and cervical ectropion.

Typical changes in the cervix are described in three women following in utero exposure to diethylstilbestrol. It is important that these changes are recognised on colposcopy and appropriate follow-up colposcopy arranged. In the absence or cervical intraepithelial neoplasia, local destructive therapy is not indicated as this may be associated with cervical stenosis.

Journal Article↗

PubMed1979

Effect of diethylstilbestrol on ion fluxes in oat roots.

Effects of diethylstilbestrol (DES) on ion fluxes in oat roots (Avena sativa L.) were investigated by measuring K(+) and Cl(-) absorption and K(+) efflux. DES rapidly decreased the absorption of K(+) ((86)Rb) and (36)Cl(-) by excised roots; 10(-4) molar DES inhibited Cl(-) absorption in 1 minute and K(+) absorption in 1 to 2 minutes. With a 10-minute incubation period, K(+) and Cl(-) absorption were inhibited 50% by 1.1x10(-5) molar and 8.4x10(-6) molar DES, respectively. Treatment for 3 minutes with 10(-4) molar DES caused irreversible inhibition of K(+) absorption. Increasing concentrations of KCl in the absorption media decreased the DES inhibition. Experiments with the DES analogs, DES dipropionate, dienestrol and hexestrol, showed that the steric configuration and the hydroxyl group of the DES molecule are important in determining the inhibitory capacity of the compound.DES increased the efflux of (86)Rb from excised roots only after a 10-minute lag period. In 10(-4) molar DES, roots lost 82% of their radionuclide content in 1 hour. Comparison of efflux curves for roots loaded for 20 hours and those loaded for 15 minutes suggested that DES increased the permeability of the plasma membrane after about 10 minutes and the permeability of the tonoplast after 10 to 20 minutes. Oligomycin and dinitrophenol also increased the loss of (86)Rb, but the lag period was about 4 hours.The rapid effect of DES on ion absorption and the slower effect on ion efflux suggest that DES initially inhibits ion uptake by affecting the transport mechanism at the plasma membrane in some manner other than alteration of membrane permeability.

Journal Article↗

PubMed1979

Comparison of Reductions in Adenosine Triphosphate Content, Plasma Membrane-associated Adenosine Triphosphatase Activity, and Potassium Absorption in Oat Roots by Diethylstilbestrol.

The possibility was investigated that diethylstilbestrol (DES) inhibits potassium absorption in oat (Avena sativa L. cv. Goodfield) roots by inhibiting mitochondrial functions in addition to inhibiting the plasma membrane ATPase. DES at 10(-6) molar stimulated the mitochondrial ATPase slightly, but higher concentrations had no effect. Oxidative phosphorylation by isolated mitochondria was inhibited 50% by 2.6 x 10(-5) molar DES; concentrations of 10(-4) molar or greater were completely inhibitory. After a lag of about 2 minutes, 10(-4) molar DES produced a linear decrease in ATP content of excised roots. After 20 minutes, the ATP content of the tissue was about 50% of the control and remained at that level after 30 minutes in DES.Comparison of changes in ATP content, plasma membrane ATPase activity, and K(+) absorption rate with time in the presence of DES showed that the rapid decrease in K(+) absorption rate corresponded more closely with the decrease in ATPase activity than the decrease in ATP content. Total inhibition of the ATPase was calculated by multiplying together the percentage decreases in ATPase activity and ATP content. At times greater than 10 minutes this "net" ATPase activity corresponded very closely with the K(+) absorption rate.These results show that DES can inhibit potassium absorption by reducing mitochondrial ATP production in addition to inhibiting the plasma membrane ATPase. However, the rapid (less than 5 minutes) inhibition of absorption is caused by direct inhibition of the ATPase rather than a reduced ATP supply because the ATP content is lowered only slightly whereas the ATPase is inhibited dramatically in that time. The relationship between plasma membrane ATPase activity and K(+) absorption rate as inhibited by DES supports the hypothesis that the ATPase is involved in cation absorption by plant roots.

Journal Article↗

PubMed1982

Phase Shifting of the Circadian Clock by Diethylstilbestrol and Related Compounds in Neurospora crassa.

Phase shifts of the circadian conidiation rhythm in Neurospora crassa were induced by 3-hour treatments of mycelia in liquid medium with diethylstilbestrol (DES), dienestrol (DIE), hexestrol (HEX), diethylstilbestroldipropionate (DESP), and dienestroldiacetate (DIEA). Over a 24-hour period beginning 24 hours after the transition from light to constant dark, maximum phase shifts occurred about 36 hours. DES was the most effective of the drugs tested, giving 10-hour phase advances at 20 micromolar. DIE and HEX caused similar phase shifts as DES at 40 micromolar. The two derivatives of the last, DESP and DIEA, were much less effective in shifting phase; only a few hours of phase advance result from treatments at 80 micromolar concentrations.The activity of isolated plasma membrane ATPase was inhibited by DES and partially by HEX, but not by DIE, DESP, or DIEA. O(2) consumption of the mycelia was inhibited equally by DES, DIE, and HEX, while DIEA and DESP had little effect. Phase-shifts by DES cannot be interpreted as evidence that plasma membrane ATPase is a component of the circadian clock.

Journal Article↗