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PubMed1985

Ovarian progesterone synthesis and content and plasma progesterone levels in adult mice treated with diethylstilbestrol neonatally.

Ovaries from 8-week-old female NMRI mice, treated with 5 micrograms diethylstilbestrol (DES) daily for the first 5 days after birth were studied for progesterone synthesis in vitro, using 3H-pregnenolone as precursor, and assayed for progesterone content using radioimmunoassay (RIA) technique. The plasma levels of progesterone were measured with RIA. These results were compared with those from control ovaries from females in different phases of the estrous cycle. Values for radioactivity representing 3H-progesterone were significantly higher after 1-hour incubation of ovarian homogenate from DES treated females than in homogenates of ovaries from any phase of the normal estrous cycle. The ovarian content of progesterone was similar in DES exposed ovaries and ovaries from females in proestrous or estrous but lower in DES ovaries than in diestrous ovaries. The plasma levels of progesterone were in the same range in DES treated females and diestrous females but higher in DES females than in estrous or proestrous females.

Animals↗

PubMed1985

[A case of vaginal adenocarcinoma after uterine exposure to diethylstilbestrol].

From 1946 to 1971, diethylstilbestrol, a nonsteroid synthetic estrogen, came in for widespread use in the USA, and in other countries only occasional use, for the treatment of high-risk pregnancies. In 1971 a retrospective epidemiologic study showed a close association of this therapy with occurrence of vaginal and cervical adenocarcinoma in young women (mean age 19 years). Up to 1981 63% of 429 clear cell carcinomas of the vagina and cervix were related to DES exposure in utero in the USA. Following reports on a few cases in other countries, the present report is the first in a Swiss female, aged 23, with stage III DES-induced adenocarcinoma of the vagina. The risk of DES-related adenocarcinoma is estimated at about 1%, but benign teratogenic lesions are present in over 50% of patients. Vaginal adenosis is the most frequent finding, but other malformations of vagina (septa), cervix, uterus and fallopian tube may be found. Malformations of the genital tract have also been described in DES-exposed male offspring.

Adenocarcinoma↗

PubMed1985

Long-term responses of the mouse uterus to neonatal diethylstilbestrol treatment and to later sex hormone exposure.

The effects of ovariectomy at 1 month of age and continuous 17 beta-estradiol (E2) and/or progesterone (P) replacement on the uterus of BALB/cCrgl mice neonatally treated with diethylstilbestrol [(DES) CAS: 56-53-1; alpha-alpha'-diethyl-4,4'-stilbenediol] or sesame oil were recorded after 1, 4, 7, and 10 months of treatment. DES-exposed uteri were found to be hypoplastic, less responsive to the growth-promoting effects of E2, and more likely to develop smooth muscle abnormalities after continuous hormonal treatment than similarly treated control uteri. Neonatal DES treatment led to leukocytic infiltration, disruption in the organization of the inner circular smooth muscle layer, and development of a population of epithelial cells believed to respond to later E2 treatment by proliferation and stratification (squamous metaplasia). Qualitative and quantitative responses to continuous P treatment and the development of cystic glandular hyperplasia and adenomyosis were found to be unaltered by neonatal DES administration. The relevance of these results to the problems of uterine abnormalities observed in women exposed to DES in utero is discussed.

Age Factors↗

PubMed1985

Inhibition by 3-amino-1H-1,2,4-triazole of hepatic tumorigenesis induced by diethylstilbestrol alone or combined with N-nitrosobutylurea in WF rats.

Six groups of inbred male WF rats were castrated at 40 days of age. Group 1 was given no further treatment; groups 3-6 received sc implantations of 5.0 mg diethylstilbestrol [(DES) CAS: 56-53-1]. At 50-55 days of age, groups 5 and 6 were given drinking water containing 5.0 mg N-nitrosobutylurea [(NBU) CAS: 869-01-2] per day for 30 days. After the termination of NBU treatment, groups 2, 4, and 6 were given 3-amino-1H-1,2,4-triazole (AT), considered an inhibitor of hydroperoxidases, in the drinking water throughout the experiment. Castrated male rats or rats castrated and treated with AT alone developed neither hepatic tumors nor pituitary tumors. The hepatic tumor incidence, the size and total number of hepatic tumors, and the mean liver weight were significantly reduced in rats given the DES-NBU combination and slightly reduced in rats given DES alone when AT was administered. In contrast, AT treatment did not change the pituitary tumor incidence and the mean pituitary weight. The thyroid gland weights were approximately 7-44 times greater in AT-treated groups than those in each corresponding control group. These data indicate that AT inhibited hepatic but not pituitary tumorigenesis and caused enlargement of the thyroid gland. The present study, therefore, provides evidence that the metabolic activation of DES by oxidation is involved in rat liver carcinogenesis.

Amitrole↗

PubMed1986

Deceased numbers of spindle and cytoplasmic microtubules in hamster embryo cells treated with a carcinogen, diethylstilbestrol.

Diethylstilbestrol (DES) has been shown to induce neoplastic transformation in the absence of measurable mutations at specific loci in Syrian hamster embryo cells. It has been proposed that DES induces cell transformation via the production of aneuploidy. In the present study we document that concentrations of DES that cause aneuploidy also produce abnormal or arrested mitotic spindles. Thus, DES may disrupt spindle microtubules and produce aneuploidy that results in disordered gene expression and eventual neoplastic transformation.

Aneuploidy↗

PubMed1986

Sperm counts and reproductive tract lesions in male Syrian hamsters exposed in utero to diethylstilbestrol.

Pregnant hamsters were administered diethylstilbestrol (DES) orally on day 14 of gestation. Sperm counts from F1 adult males were lower than controls. Significant and consistent lesions were confined to the epididymides of DES exposed males, in which epididymal granulomas were the most common lesion. Epididymal granulomas of the tail have been associated with a bacterial etiology while granulomas of the head may be related to blind ductules or a lack of ductule connection.

Animals↗

PubMed1985

Diethylstilbestrol inhibits tumor growth and prolactin production in rat pituitary tumors.

Treatment of rats bearing transplantable MtT/W15 tumors with 10 mg of diethylstilbestrol (DES) for 3 weeks led to inhibition of tumor growth. The inhibition of tumor growth was reversible after removal of the DES. Histologic examination revealed decreased mitotic activity; however, DES did not produce cell necrosis. Concomitantly, the anterior pituitary glands of animals treated with DES became hyperplastic, with an increased number of prolactin (PRL)-producing cells. DES resulted in a decreased number of PRL cells in the tumor and decreased serum PRL/tumor weight, compared with that of control rats. There was also an increase in the number of growth hormone (GH) tumor cells and an increased serum GH/tumor weight. 17 beta-Estradiol had an effect similar to that of DES, while progesterone did not inhibit tumor growth or cause pituitary cell hyperplasia. Ovariectomy resulted in a decrease in the tumor growth rate, compared with that of control animals, suggesting that the MtT/W 15 tumors are relatively dependent on estrogens for optimal growth. These results indicate that DES inhibition of MtT/W 15 tumor growth is an excellent model for study of the mechanism of the inhibition of tumor growth and the modification of GH and PRL expression by the tumor cells.

Animals↗

PubMed1985

Extracellular distribution of radiolabel obscures specific binding of diethylstilbestrol in mouse skeletal muscle.

The extracellular distribution of 3H-diethylstilbestrol (3H-DES) in mouse skeletal muscle was assessed following intraperitoneal injection. Total muscle extracellular space was measured with 14C-inulin, and the vascular space with 125I-albumin. A significant difference in the distribution of native 3H-DES and its metabolites in muscle and blood was found. This could only be explained if these compounds distributed with the albumin space and not the inulin space.

Albumins↗

PubMed1985

Endometrium cell surface abnormalities in the Syrian hamster as a result of in utero exposure to diethylstilbestrol.

Scanning electron microscopy (SEM) was used to observe changes in the hamster endometrium cell surface following in utero pre- and/or postnatal exposure to diethylstilbestrol (DES). Some of the changes in cell surfaces are associated with alterations in cell sizes and shapes (from columnar to cuboidal and/or squamous) and in microvilli and mucous secretion. In all cases, DES treated uteri show mucosal cell surface pleomorphism, apocrine secretion and cystic accumulation of secretory material. Microvillous pleomorphism and peculiar linkages attaching one microvillus to others were investigated. Although the function and nature of such linkages is unclear, their presence seems to be more prominent in the in utero DES treated hamster endometrium. These infrastructures may provide a support for the microvilli distributed on the mucosal cell surfaces, i.e., a morphological compromise between the single microvillous surface and the microridged structures. These interconnections may represent glycocalyx material or remodeling of cell surfaces toward squamous epithelium.

Animals↗

PubMed1985

Diethylstilbestrol selectively modulates plasma coagulation protein synthesis by the perfused rat liver.

The combined effects of orchiectomy and estrogen administration on synthesis of selected hepatic secretory proteins--antithrombin (AT) III, plasminogen, fibrinogen, factor II (prothrombin), factor VII, fibronectin, and albumin--were studied using the isolated rat liver perfused in vitro for ten hours. Male rat liver donors underwent orchiectomy under ether anesthesia and then received 5.0 mg of diethylstilbestrol (DES) by subcutaneous pellet implantation or a placebo pellet; 14 days later the livers were extracted and perfused in vitro for ten hours. In DES experiments, 1.0 mg of DES was also added directly to the liver perfusate at the outset. Pretreatment with DES resulted in significant increases in cumulative synthesis of factors II (65%) and VII (76%) and significant reduction in cumulative synthesis of both antithrombin III (20%; P = .03) and plasminogen (27%; P less than .01) compared to control perfusions, but synthesis of fibrinogen, fibronectin, and albumin was not significantly affected by addition of the hormone. Plasma samples collected from rat liver donors that had received DES showed similar effects on protein concentrations: significant decreases in concentration of plasminogen and antithrombin III were apparent with no significant changes in concentrations of fibrinogen, fibronectin, or albumin. In additional perfusions, "dose-response" experiments were conducted in which rat liver donors received a subcutaneous DES pellet of 0.5, 5.0, or 50 mg. Synthesis of plasminogen in this group of perfusions was progressively decreased as the concentration of DES administered to the rat liver donor increased. Synthesis of AT III was reduced to the same degree by 5.0 or 50 mg of DES, both being substantially lower than the 0.5-mg experiments. Concentrations of these two proteins in plasma samples from rat liver donors showed changes quite similar to those seen in perfusion experiments; however, plasma fibrinogen concentrations were not different among the three groups of rats.

Animals↗

PubMed1985

Effect of diethylstilbestrol on the frequencies of sister chromatid exchange in vitro and in vivo.

The influence of diethylstilbestrol (DES) on the SCE frequency was studied in various cell systems (V79, HTC, DON, WI-38, human lymphocytes) differing in their ability to metabolize the two promutagens benzo(a)pyrene and cyclophosphamide as well as after incubation with exogenous metabolic systems (S9 mix and peroxidase/H2O2) and in vivo on cells from the bone marrow of the Chinese hamster. DES concentrations from 10(-6) to 10(-4) M were tested. Slight SCE induction was observed only at the highest concentration (10(-4) M) of DES in human lymphocytes treated with DES for the entire culture period of 72 h and in DON cells. No increase of the SCE rate was determined in the other cell lines and in vivo. The combination with S9 mix or peroxidase/H2O2 also had no influence on the SCE frequency. These findings cast doubt on the assumption that DES is metabolized to a DNA-damaging compound subsequently leading to SCE induction. The positive findings in the SCE test are more likely to be products of an indirect and rather unspecific effect.

Animals↗

PubMed1985

Lesions of the rete testis in mice exposed prenatally to diethylstilbestrol.

Adenocarcinoma of the rete testis is an exceptionally rare and malignant testicular neoplasm. Although treatment of pregnant women with diethylstilbestrol (DES) results in reproductive tract abnormalities in their male offspring, increased incidence of testicular tumors has not been verified. However, recently three cases of seminoma have been described in men prenatally exposed to DES, suggesting an association of prenatal DES treatment and the subsequent development of testicular tumors. This report describes the treatment of outbred pregnant CD-1 mice with DES (100 micrograms/kg) on Days 9 through 16 of gestation and its effects on their male offspring. In addition to nonmalignant abnormalities such as retained testes which have been reported in men exposed prenatally to DES, lesions resembling adenocarcinoma of the rete testis were seen in prenatally DES-treated mice at 10 to 18 mo of age (11 of 233; 5%). No comparable lesions were seen in 96 age-matched control male mice. These results suggest an association of prenatal DES exposure and the subsequent development of testicular lesions in the rete testis of mice.

Adenocarcinoma↗

PubMed1985

Diethylstilbestrol metabolites and analogs. Biochemical probes for differential stimulation of uterine estrogen responses.

Diethylstilbestrol (DES) and certain chemically structural derivatives and analogs, indenestrol A (IA), indenestrol B (IB), indanestrol (IN), and pseudo-DES (PD), have been used as probes to examine various estrogenic responses previously considered interrelated and obligatory to the stimulation of uterine growth. All the analogs had poor uterotropic activity in vivo which ranged from 10-200 times less than that of estradiol or DES. The poor uterotropic activity was not due to poor binding affinity for the receptor. All compounds except IN interacted with the mouse uterine estrogen receptor with high affinity (approximately Ka 1.5-2.2 X 10(10) M-1). In addition, the compounds were able to translocate similar levels of receptor to the nucleus in vivo. Nuclear retention and occupancy of the estrogen receptor by the compounds was comparable to the patterns produced by DES or estradiol. The activity of uterine tissue responses was investigated during treatment with the compounds. Only IA stimulated uterine glucose-6-phosphate dehydrogenase to significant levels similar to DES or estradiol. Uterine progesterone receptor was induced to varying degrees by all compounds; the indenestrol isomers (IA and IB) were the most active. Uterine DNA synthesis was marginally stimulated by the derivatives and analogs except for IB which showed a response increase comparable to DES or estradiol. Because of the differential stimulation, these data suggest that in uterine tissue estrogen receptor stimulates certain biochemical responses independently and not in concert. The ability of a particular response to be increased may depend on the chemical nature of the ligand receptor complex and its interaction at genomic sites.

Animals↗

PubMed1985

Mineral deposition in diethylstilbestrol- and Synovex-treated steers.

The effects of diethylstilbestrol (DES) and Synovex-S hormonal growth promotants on composition of body ash deposited by feedlot beef steers were studied in two slaughter-balance trials. Trial 1 consisted of three groups of eight Hereford steers averaging 225 kg initial body weight. One group was initially slaughtered (IS) at the beginning of the trial and two groups, control (C) and DES-treated (20 mg/steer daily in diet), were fed for 177 d and then slaughtered. Trial 2 consisted of 28 Hereford steers averaging 310 kg initial body weight. Four steers were IS and 24 steers were assigned to a factorial arrangement of treatments (- or + Synovex-S ear implant and - or + dietary kiln dust), fed for 126 d and slaughtered. Each Synovex-S ear implant contained 200 mg progesterone and 20 mg estradiol benzoate. Kiln dust (KD) was fed as a digestive tract buffer, and the +KD diets contained 1.23% Ca and .37% P compared with .45% Ca and .36% P in -KD diets on an as-fed basis. Mineral concentration in body tissue was greater for IS than for fed steers reflecting deposition of soft tissue, particularly fat, during the feeding period. Mineral concentration in body tissue was similar between C and hormonally-treated steers. Mineral composition of tissue ash in IS, C and hormonally-treated steers and composition of ash deposited during the feeding period for C and treated steers were similar. The results suggest that both DES and Synovex treatments of beef steers do not cause an increased propensity for skeletal growth but that ash deposition is of similar composition in C and treated steers.

Animals↗

PubMed1979

Vaginal adenosis in stillborns and neonates exposed to diethylstilbestrol and steroidal estrogens and progestins.

A histologic study was conducted of sagittal sections of the genital tracts of 281 autopsied female stillborns and neonates. The prevalence of vaginal adenosis among 43 offspring exposed in utero to diethylstilbestrol (DES) was 70%, a frequency 18 times greater than the 4% prevalence among 159 unexposed offspring. The relationship of the prevalence of vaginal adenosis to the gestational age at initial exposure was highly significant: 81% of those first exposed during the period of vaginogenesis had adenosis, whereas none exposed after 21 weeks' gestation had adenosis (P1 = 1 X 10(-4)). The relationship of the prevalence of vaginal adenosis to the total dose of DES prior to 22 weeks' gestation also was significant (P1 = 0.02), and this relationship was independent of gestational age at first exposure (P1 =0.01). In contrast, the prevalence of adenosis among 23 offspring exposed to steroidal estrogens and progestins was about the same as that among the unexposed offspring. Vaginal adenosis was unrelated to the complications of pregnancy for which the hormones were given, the calendar year of birth, and the gestational age at delivery.

Diethylstilbestrol↗

PubMed1979

The effects of prenatal diethylstilbestrol (DES) exposure on the genitalia of pubertal Macaca mulatta. I. Female offspring.

Nineteen pregnant female rhesus monkeys (Macaca mulatta) received 1 mg/day diethylstilbestrol (DES) over three time periods during gestation: day 21 to delivery (group I), day 100 to delivery (group II) and day 130 to delivery (group III). Seven females and five males of a total of 20 offspring are presently alive at 5 1/2 years of age; one female died at 5 years of age. No deaths have been shown to be treatment related. In female offspring, menstruation began at about 2 1/2 years of age, was irregular for approximately one and one-half to two years and then became regular. Vaginal ridging and/or cervical hooding have been observed in seven of the eight DES-exposed females, and three had histologically demonstrable vaginal adenosis. None of the anomalies was related to a specific treatment period, for they appeared in all treatment groups, nor did they occur in the age-matched controls. Furthermore, none of the animals, either treated or control, showed any evidence of adenocarcinoma. Therefore, exposure of Macaca mulatta females to DES in utero appears to be teratogenic, but thus far no carcinogenicity has been observed. Reports in humans indicate that adenocarcinoma is an additional manifestation of prenatal exposure to DES; also, treatment effects appear to be more commonly observed in individuals exposed during the early stages of gestation. From this viewpoint, the rhesus monkey is a potentially valuable model for the study of vaginocervical anomalies and adenosis, but it is premature to consider it a suitable model for the study of adenocarcinoma.

Animals↗

PubMed1979

Menstrual history of young women exposed in utero to diethylstilbestrol.

The menstrual histories of 218 patients exposed in utero to diethylstilbestrol (DES) were compared with those of 158 control subjects. No significant differences were revealed in the complaint of menstrual irregularities at either the initial or follow-up examination. Age at menarche was the same in both groups, and was the same as found in the United States as a whole. These findings differ from the report of a controlled trial in Chicago which suggests that there is a specific pattern of oligomenorrhea associated with DES exposure.

Adolescent↗

PubMed1973

High-dose diethylstilbestrol diphosphate therapy of prostatic cancer after failure of standard doses of estrogens.

Ten patients with metastatic prostatic cancer no longer responsive to conventional doses of estrogens (stilbestrol 15 mg. daily or equivalent) were treated with high doses of diethylstilbestrol diphosphate. Objective responses lasting from three to fifteen months were obtained in four patients; three of the patients had previously shown progressive disease following orchidectomy.Toxic manifestations consisted mainly of increased gynecomastia and water retention. No serious cardiovascular complications were encountered. This dose-response effect of estrogens indicates the persistence of hormone-dependent tumours in some patients with recurrent disease despite conventional estrogen therapy.

Body Fluids↗