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PubMed1991

Bioactivity of plasma prolactin in ovariectomized, diethylstilbestrol-treated Long-Evans and Holtzman rats after thyrotropin-releasing hormone or bromocriptine administration.

The objective of this study was to determine the effects of thyrotropin-releasing hormone (TRH) and bromocriptine on plasma levels of biologically active prolactin in ovariectomized, diethylstilbestrol (DES)-treated rats. Female Long-Evans and Holtzman rats were ovariectomized and each was given a subcutaneous implant of diethylstilbestrol (DES). One week later, groups of DES-treated rats were fitted with indwelling intra-atrial catheters, and 2 days later blood samples were withdrawn before and at 1, 2, 5, 10, and 20 min after intravenous administration of TRH (250, 500, or 1000 ng/rat). Blood samples were obtained from other groups at 4 weeks of DES treatment by orbital sinus puncture under ether anesthesia before and at 30, 60, and 120 min after bromocriptine administration (2.5 mg/rat sc). Plasma was assayed for prolactin by conventional radioimmunoassay (RIA) and by Nb2 lymphoma bioassay (BA). Holtzman rats released significantly more prolactin following TRH than did Long-Evans rats when the RIA was used to measure prolactin. However, when the BA was used to assay prolactin in the same samples, the Long-Evans rats released more prolactin than did the Holtzman rats. In addition, the ratio of the BA to RIA values was significantly increased in both strains following TRH, but the greatest increase was observed in the Long-Evans rats, in which the ratio was 4.5 at the peak of the TRH-induced rise in plasma prolactin. Gel filtration chromatography of plasma obtained at 5 min after TRH treatment in Long-Evans rats revealed large molecular forms of prolactin with BA to RIA ratios of 4-5. In addition, monomeric prolactin had a BA to RIA ratio of 2. Bromocriptine treatment reduced prolactin levels in both strains, but the effect was more rapid in Holtzman than in Long-Evans rats. In addition, bromocriptine treatment of Holtzman, but not Long-Evans, rats significantly reduced the BA to RIA ratio of plasma prolactin. The results indicate that TRH and bromocriptine affect the release of biologically active prolactin to a greater extent than prolactin detected by antibody in the RIA, and that Long-Evans and Holtzman rats respond to these secretagogues differently with regard to BA to RIA comparisons.

Animals↗

PubMed1995

The effect of neonatal exposure to diethylstilbestrol, coumestrol, and beta-sitosterol on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat.

The neonatal hormone environment influences the sexually differentiated patterns of development. Estrogens, derived from intracerebral aromatization, promote male pattern development of the central nervous system. The purpose of this study was to determine the effects of neonatal exposure to environmental estrogens on luteinizing hormone (LH) secretion and development of the sexually dimorphic nucleus of the medial preoptic area (SDN-POA) in castrated adult rats. Neonatal rats of both sexes received injections of either corn oil, 0.1 microgram diethylstilbestrol (DES), 3 micrograms beta-sitosterol (B1), 30 micrograms beta-sitosterol (B2), 0.1 microgram coumestrol (C1), 1 microgram coumestrol (C2), or 10 micrograms coumestrol (C3) on Day 1-10 of life and were castrated on Day 21. Right heart catheters were placed on Day 42, and GnRH (50 ng/kg) was administered. Blood was sampled for LH at 0-, 5-, 10-, 15-, and 30-min intervals. All doses of beta-sitosterol and coumestrol elicited increased basal levels of LH in females. In males, B1, B2, C2, and C3 increased basal levels of LH. The GnRH-induced LH increase was prevented in females treated with diethylstilbestrol and 10 micrograms of coumestrol. Males in all treatment groups exhibited GnRH-induced LH surges. The animals were sacrificed by decapitation on Day 49. Volumes of the SDN-POA of the groups were compared. Treatment with the agents did not result in significantly increased SDN volume in females; nor was there a difference in SDN size among the male groups. These data show that exposure to environmental estrogens early in development alters both postpubertal pituitary response to GnRH and basal LH secretion in females and alters only basal LH secretion in males. No significant enlargement (i.e., masculinization) of the SDN-POA was exhibited.

Animals↗

PubMed1976

Metabolism of diethylstilbestrol by rat liver: a preliminary report.

Aerobic incubation of a misture of E[1,1,1-D3]-3,4;bis(p-hydroxyphenyl)-hex-3-ene admixed with an approximately equimolar amount of unlabeled diethylstilbestrol and [ 2-(14)C ] diethylstilbestrol with rat liver homogenates in the presence of NADPH yielded water-soluble metabolites as well as products more and less polar than the starting material. Addition of 5-adenosyl-L-methionine increased the quantity of nonpolar metabolites. Incubation with rat liver microsomes yielded similar results. When polar metabolites from incubation with rat liver microsomes were incubated with catechol O-methyltransferase and S-adenosyl[methyl-3 H]-L-methionine there was conversion to 3H-labeled nonpolar products. Examination of reaction products by means of gas chronatography-mass spectrometry gave evidence for the formation of a dihydroxydiethylstilbestrol, a dihydroxydienestrol, and a monomethoxydiethylstilbestrol.

Animals↗

PubMedDate not supplied

Validation of screening method for residues of diethylstilbestrol, dienestrol, hexestrol, and zeranol in bovine urine using immunoaffinity chromatography and gas chromatography/mass spectrometry.

A method was developed, using commercially available immunoaffinity chromatography cleanup cartridges, followed by detection by gas chromatography/mass spectrometry, to screen for residues of the hormone growth promotants diethylstilbestrol, dienestrol, hexestrol, and zeranol in bovine urine. The single-laboratory, in-house validation included assessment of recoveries, repeatability, linearity of response, detection capability, and specificity (cross-reactivity) with a suite of antibiotics and other hormonal growth promotants. The method was validated for screening at a target concentration of 2.0 microg/L in urine. The detection capabilities for the analytes were diethylstilbestrol, 0.24; dienestrol, 0.15; hexestrol, 0.84; and zeranol, 0.28 microg/L.

Animals↗

PubMed1991

Carcinogenicity of diethylstilbestrol in the Wistar rat: effect of postnatal oral contraceptive steroids.

Diethylstilbestrol (DES) has been associated with vaginal neoplasia and malformations in humans. We have studied a test population of 504 female Wistar rats given diethylstilbestrol at from 0.0 to 0.5 mg/kg maternal body weight on days 18, 19, and 20 of gestation. Animals were euthanized in extremis, or at 2 years of age. The incidence of vaginal epithelial tumors was dose related. The types of epithelial tumors of the vagina were adenocarcinoma, squamous cell carcinoma, and mixed carcinoma, containing discrete adenomatous and squamous components. The incidence of vaginal epithelial tumors was determined to be dose related: rats exposed to 0 mg DES/kg maternal weight had an incidence of 0.6% (1 of 167 rats); 0.1 mg/kg, 4.1%; and 0.5 mg/kg, 4.3% (6 of 140); 25 mg/kg, 1.6% (1 of 63); and 50 mg/kg, 11.5% (3 of 26). Tumors of other reproductive tissues (mammary gland, ovary, oviduct, cervix, or uterus) demonstrated no discernible DES dose-response relationship. There was no oncogenic effect of postnatal administration of oral contraceptives (0 oral contraceptives, 31.25 micrograms/kg diet ethynylestradiol, and 31.25 micrograms/kg diet norethindrone or 104 micrograms/kg diet ethynylestradiol and 31.25 micrograms/kg diet norethindrone). Thus, vaginal tumors can be induced in a dose-related manner in the rat following in utero DES exposure. Oral contraceptive treatment did not increase the risk of neoplasia.

Adenocarcinoma↗

PubMed1987

Human papillomavirus associated with vaginal intraepithelial neoplasia in women exposed to diethylstilbestrol in utero.

Five out of 959 young women, exposed to diethylstilbestrol (DES) in utero, developed vaginal intraepithelial neoplasia while they were under follow-up in the Diethylstilbestrol-Adenosis Project at Baylor College of Medicine, Houston, Texas. We suggest that the development of the vaginal intraepithelial neoplasia at a younger age than usual may be caused by a higher susceptibility of the DES-exposed patient to factors associated with the development of intraepithelial neoplasia. A common finding in all five women was the detection of the deoxyribonucleic acid (DNA) of human papillomavirus types 6 or 16 in their lesions, using high-stringency in situ hybridization. The role of human papillomavirus and herpes simplex virus in the etiology of intraepithelial neoplasia is discussed. Close follow-up is recommended for DES-exposed patients, especially those who have risk factors known to be associated with genital neoplasia.

Adolescent↗

PubMed1987

[The induction of sister chromatid exchange by diethylstilbestrol and mitomycin C in lymphocytes of mothers and their newborn infants].

Lymphocytes of mothers and their newborn infants were treated with varying concentrations of diethylstilbestrol (10(-6) M, 10(-5) M and 10(-4) M) and mitomycin C (0.003, 0.009 and 0.03 microgram/ml), and the incidence of sister chromatid exchanges (SCE) was determined. The results showed that the spontaneous SCE rate in the newborns is less than that of their mothers. A dose-related increase in SCEs was observed in cells exposed to the alkylating chemical mitomycin C, while increases in SCEs were not noted in cultures exposed to diethylstilbestrol. No different susceptibilities of lymphocytes from mothers and newborns to the chemical induction were observed.

Diethylstilbestrol↗

PubMed1986

[Direct determination of diethylstilbestrol and its monoconjugates in plasma].

Direct Determination of Diethylstilbestrol and its Monoconjugates in Plasma After "homogeneous ion pair extraction" with CH3OH from plasma of patients suffering from metastatic prostate cancer and subsequent partitioning on a C18-phase diethylstilbestrol (E-DES) and its monoconjugates (glucuronide, sulfate) as well as its glucuronide-sulfate conjugate may be detected quantitatively by HPLC/UV (236 nm) or HPLC/ED (+1.0 V). Working electrode is a special home-made carbon paste electrode. The range of detection is in the low ng range (2-5 ng/ml plasma); standard deviation is less than 5%. It is the first time that plasma levels of these metabolites of fosfestrol (Honvan) could be measured directly without prior hydrolysis.

Chromatography, Liquid↗

PubMed1986

Cytokinetic parameters of locally advanced human breast cancer treated with diethylstilbestrol and chemotherapy.

Thirty-six patients with locally advanced breast cancer received diethylstilbestrol (1 mg/die) for 3 days followed by FAC (5 Fu 600 mg/m2, adriamycin 50 mg/m2, cytoxan 600 mg/m2) on day 4, q. 21 days. After three cycles, responsive patients were submitted to surgery. Tumor kinetic parameters were evaluated by TLI and PDP-LI in 22 patients on serial tumor biopsies at diagnosis (TO), after DES (T1), 24 hrs after the first FAC (T2) and at the time of radical surgery (T3). An estrogenic recruitment was evident by TLI in 9/22 tumors and by PDP-LI in 16/22 patients. Our results demonstrate that diethylstilbestrol can induce a kinetic recruitment of breast cancer cells independently from their ER content and that chemotherapy is able to stop cell proliferation.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1979

Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) project.

Initial clinical findings are reported for the 3339 young women enrolled in the Diethylstilbestrol Adenosis (DESAD) project. Changes in the vaginal mucosa (VEC--vaginal epithelial changes), which were detected by colposcopy or iodine staining, occurred in 34% of 1275 participants identified by review of prenatal records 59% of participants who themselves requested entry into the project, and 65% of participants referred by a physician. Analysis of data on the 298 women who were identified by record review and whose prenatal records contained complete information about drug exposure indicated that VEC is most closely associated with the timing of the onset of intrauterine exposure to diethylstilbestrol (DES), total dose, and length of exposure. Frequency of VEC was also found to decrease with age. No instances of severe dysplasia, carcinoma in situ, invasive squamous cell adenocarcinoma, or clear cell carcinoma were observed among the women identified by record review.

Adenocarcinoma↗

PubMed1979

Effect of steroids and diethylstilbestrol on cocaine toxicity, plasma concentrations and urinary excretion.

Comparative experiments were performed on female rats given pregnenolone-16 alpha-carbonitrile (PCN), spironolactone, triamcinolone, estradiol or diethylstilbestrol to study correlations between the toxic effect of cocaine, its blood clearance and its urinary excretion. PCN and estradiol significantly reduced the toxicity of the drug as well as its plasma levels and urinary excretion. Diethylstilbestrol and spironolactone, unlike triamcinolone, also diminished cocaine toxicity and plasma concentrations.

Animals↗

PubMed1984

Effects of diethylstilbestrol and cyclophosphamide on the pathogenesis of experimental Cryptococcus neoformans infections.

Treatment of mice with a single dose of cyclophosphamide 24 h before challenge with Cryptococcus neoformans increased host survival, whereas treatment with 10 daily exposures of cyclophosphamide, starting 2 days before challenge, markedly reduced survival in mice challenged on the second day of drug treatment. Treatment with 14 daily exposures of diethylstilbestrol before challenge with C. neoformans did not markedly affect host survival. A correlation was sought between the distribution of radiolabeled C. neoformans and host survival. Radiolabeled C. neoformans administered intravenously was cleared rapidly from the blood of naive mice and accumulated in the lungs, liver and kidney within 1 h. The radiolabeled yeasts were subsequently cleared from the lungs. The distribution of radiolabeled C. neoformans among organs was generally the same in control mice and mice treated with diethylstilbestrol of various cyclophosphamide regimens after 3 or 24 h. The distribution of C. neoformans measured as colony forming units was generally in agreement with results from radioactivity measurements for animals sacrificed 3 or 24 h after challenge. One week after challenge, C. neoformans colonies were grown from the brain, liver and kidneys. C. neoformans was found in the brain within 1 h after i.v. challenge, suggesting that the central nervous system disease in mice challenged i.v. resulted from a primary infection of the brain.

Animals↗

PubMed1984

Disruptive effect of diethylstilbestrol on microtubules.

Diethylstilbestrol, a unique carcinogen lacking measurable mutagenic potency in Salmonella, was shown to be an inhibitor of microtubule assembly in vitro using microtubule proteins isolated from porcine brains. The effective concentration of diethylstilbestrol was 10-200 microM, as determined by viscometry, turbidity measurement, and electron microscopic analysis.

Animals↗

PubMed1983

Modified method for electron capture gas-liquid chromatographic determination of diethylstilbestrol residues in urine of fattened bulls.

A gas-liquid chromatographic (GLC) method with electron capture (EC) detection was developed for determining diethylstilbestrol residues in the urine of fattened bulls. Diethylstilbestrol (DES) is extracted into benzene, and then into 1N sodium hydroxide. The pH of the phenolic fraction (alkaline phase) is adjusted to 10.2 and DES is extracted again into benzene. Sample extracts are cleaned up on silica gel. Trifluoroacetic anhydride (TFAA) is used as acylation reagent, and the derivatized sample is chromatographed on a 3% OV-17 column and measured with a 63Ni EC detector. The method is suitable for determining residues at levels as low as 2 ppb.

Animals↗

PubMed1984

Self-concept in the diethylstilbestrol daughter.

To evaluate the possible psychologic impact of diethylstilbestrol (DES) in utero exposure on young women, the authors studied self-concept as a multifaceted construct in 25 known DES in utero exposed young women compared with 25 age-matched controls. Psychologic inventories used included Rosenberg's Self-Esteem Scale, Adjective Check List, Who Am I Test, Wyeth 's Self-Satisfaction Ladder, and the Draw Yourself Test, as well as semi-structured personal interview. Diethylstilbestrol subjects differed significantly from controls on the adjective check list subscales of Defensiveness, Nurturance, and Affiliation (P less than or equal to .05), as well as in the Draw Yourself Test, by omitting or obscuring body parts, especially sexual characteristics (P = .001). Subjects with known physical sequelae associated with DES were less satisfied with their lives (P = .05). On other measures of self-concept, no peer differences between DES subjects and controls were found. In fact, a trend for DES subjects to describe themselves more positively emerged. Most women also mentioned that they trusted physicians and were concerned about their future fertility and about the possibility of developing cancer. These findings suggest that young women exposed to DES may be using protective denial in their attempt to cope with their DES exposure. Physicians need to be aware of the possible psychologic impact of DES exposure, especially as more data become available regarding decreased fertility in these women and as new attention is focused on young men exposed to DES in utero.

Adolescent↗

PubMed1983

Health risks and effects of prenatal exposure to diethylstilbestrol.

Patients exposed prenatally to diethylstilbestrol have been shown to have a number of significant health risks that may be considered in the evaluation of this population. Neoplastic lesions of the cervix and vagina have been observed in a few patients. Increased prevalence of squamous intraepithelial neoplasms has been reported by several large clinical centers, and a recent observation of ovarian neoplasms has been reported. The significance of these observations remains to be substantiated. Anatomic deformities of the cervix, vagina, uterus, and fallopian tubes have been associated with increased pregnancy loss or infertility. The epithelial abnormalities of adenosis and cervical erosion essentially hallmark prenatal exposure to diethylstilbestrol. These changes are in themselves not malignant or premalignant and rarely warrant therapy (Figure 1).

Abnormalities, Drug-Induced↗

PubMed1982

Inhibition of the R3327MAT-Lu prostatic tumor by diethylstilbestrol and 1,2-bis(3,5-dioxopiperazin-1-yl)propane.

We have previously described the inhibitory effects of diethylstilbestrol on the growth of the androgen-independent, anaplastic Copenhagen rat prostatic tumor, R3327AT, which has a low metastatic potential. We have now selected a variant of the R3327AT tumor that metastasizes exclusively to the lungs, and we have designated it the R3327MAT-Lu. In a dose-response protocol, diethylstilbestrol was inhibitory to the primary R3327MAT-Lu tumor, thereby also inhibiting the formation of lung metastases. Inhibition was also observed in this model tumor by the chemotherapeutic agent 1,2-bis(3,5-dioxopiperazin-1-yl)propane.

Animals↗

PubMed1981

Effect of treatment with diethylstilbestrol-polyestradiol phosphate or estramustine phosphate (estracyt) on natural killer cell activity in patients with prostatic cancer.

We evaluated the effect of treatment of patients with prostatic cancer with estramustine phosphate or the combination diethylstilbestrol-polyestradiol phosphate on the natural killer cell activity in peripheral blood. Although estramustine phosphate did not affect natural killer cell activity, diethylstilbestrol-polyestradiol phosphate substantially reduced natural killing after a treatment period of 1 week. The activity was only slightly further lowered after 4 weeks of treatment. Possible clinical implications of the difference in susceptibility of natural killer cells to these agents are discussed.

Aged↗