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PubMed2003

Effects of maternal exposure to diethylstilbestrol on the development of the reproductive system and thyroid function in male and female rat offspring.

Diethylstilbestrol (DES) was administered subcutaneously at 1.5 or 15 microg/kg/day (DES 1.5 group, DES 15 group) to pregnant SD rats daily on days 7-21 of gestation to investigate its effects on the development and functions of the reproductive system and thyroid gland in their offspring. Of the 11 pregnant rats in the DES 15 group, only one delivered a live pup. Rat pups in the DES 1.5 group were autopsied at 1, 3, or 6 weeks after birth. In the DES 1.5 group, the plasma T4 concentrations at all weeks of age at autopsy were significantly increased, the TSH concentration at 6 weeks of age was also significantly increased, and the height of thyroid follicular epithelial cells was increased at 3 weeks. The testosterone concentration in the DES 1.5 group at 6 weeks was significantly decreased and the plasma LH concentration was increased. The DES treatment increased the plasma FSH concentration in female pups at 3 weeks, increased the percentages of primary and secondary ovarian follicles, and decreased the percentage of primordial follicles, but did not influence the timing of the vaginal opening or the onset of the estrous cycle. These observations indicate that prenatally administered DES increases thyroid function, and has an inhibitory effect on testicular function and a promoting effect on female reproductive function.

Animals↗

PubMed2005

Effects of maternal exposure to a low dose of diethylstilbestrol on sexual dimorphic nucleus volume and male reproductive system in rat offspring.

Diethylstilbestrol (DES) was administered subcutaneously at 0.5, 1.5 or 4.5 microg/kg/day (DES 0.5, 1.5 and 4.5 groups, respectively) to pregnant SD rats daily on days 7-21 of gestation, to investigate its effects on the development and functions of the reproductive system in their male offspring. Of the 10 pregnant rats in the DES 4.5 group, only 1 delivered, and this rat could not suckle the pups. Rat pups in the DES 0.5 and 1.5 groups were autopsied at 1, 3, 6 and 15 weeks after birth. The testosterone concentrations in the DES 1.5 and 0.5 groups at 6 weeks were significantly decreased and the plasma LH concentrations were not altered. In the DES 1.5 group, DES treatment did not change the volume of the sexually dimorphic nucleus in the preoptic area (SDN-POA) in the male offspring, although this dose of DES increased the volume of SDN-POA in female offspring. The DES treatment altered frequencies in the cycles of the seminiferous tubules, and suppressed histological maturation in the epididymis and the prostate weight. These observations indicate that prenatally administered DES impairs testicular endocrine function continuously as well as pituitary function, but the induced low level of testosterone disrupts spermatogenesis and permanently inhibits the morphological development of epididymis and prostate.

Animals↗

PubMed2006

Expression of estrogen-regulated genes during development in the mouse uterus exposed to diethylstilbestrol neonatally.

Neonatal diethylstilbestrol (DES) exposure elicits a wide range of abnormalities in the female mouse genital tract. This animal model system is suitable for investigating the mechanism of DES syndrome in humans. Accumulated evidence has shown that critical periods in development are present for distinct and permanent alterations in the female genital tract of mice exposed to DES neonatally (DES-mice). These effects of DES and other estrogens are mainly mediated by estrogen receptor alpha (ER alpha) through multiple pathways. Induction of ER alpha by DES exposure in neonatal stromal and epithelial cells, and successive premature activation of estrogen-regulated genes are thought to be essential to induce the abnormalities. Induction of malformation, permanent changes in estrogen-regulated genes, such as protooncogenes and growth factors, and carcinogenesis are assumed to be interdependent. This review focuses the following topics to discuss the molecular basis of DES-induced abnormalities mainly based on the results by histochemical techniques in the uterus: spatiotemporal expression of ER alpha and coactivators, proteins relating morphogenesis, and estrogen-regulated protooncogenes and growth factors.

Animals↗

PubMed1981

Effect of diethylstilbestrol on tissue gain and carcass merit of feedlot beef steers.

The effect of diethylstilbestrol (DES) on the composition of tissue gain of Hereford steers was studied in a complete slaughter balance trial. Eight steers were slaughtered initially (IS) and, after 177 days on feed, eight control steers (C) and seven steers that had been fed 20 mg DES daily (DES) were slaughtered. Initial full body weight averaged 224.8 kg, and final full body weight averaged 403.0 kg for the C steers and 433.6 kg for the DES steers. Final empty body weight averaged 346.6 kg for the C steers and 368.0 kg for the DES steers. DES improved live weight gain by 17% and conversion of feed dry matter to live weight by 12%. Recovery of wet weight during slaughter averaged 99.6%. DES steers had larger rib cut weights and greater proportions of separable lean and bone plus connective tissue in the rib cuts than C steers, an ribeye area tended to be larger in DES steers. DES caused a small shift in relative body composition toward more protein, moisture and ash. Tissue gain in DES steers consisted of 28.3% more protein, 26.0% more moisture, 73.2% more ash, 1.5% less fat and 109.1% more residual (dry matter not accounted for by N x 6.25, ether extract and ash) than did tissue gain in C steers. Energy gain per unit of energy intake over the feeding period was not affected by DES treatment, but DES improved protein gain per unit of protein intake and per unit of energy intake by approximately 20% within the total empty body and by about 25% within the carcass fraction. Results confirm indirect estimates in the literature indicating that DES increases skeletal growth and lean tissue deposition in feedlot steers.

Animal Feed↗

PubMed1997

Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group.

Between 1984 and 1989, 197 patients with T1-4, NX, M1, G2-3 or G3 prostate cancer were randomized to treatment with 560 mg estramustine phosphate (EMP, Estracyt, Emcyt) or 3 mg diethylstilbestrol (DES) per day in a double blind study with stratification on presence or absence of cancer pain at start. A total of 194 patients were evaluated for efficacy of therapy. Time to progression (p = 0.054), to treatment failure (p = 0.036), cancer-specific survival (p = 0.068) as well as overall survival (p = 0.021) were longer in the DES group. There were more patients with prognostic parameters indicating bad prognosis in the EMP group. This trial was designed to study whether EMP had better effect than DES as the primary treatment of high-grade, disseminated prostate cancer. The results did not confirm this hypothesis. On the contrary, treatment with DES had relatively good effect on this very aggressive form of prostate cancer.

Antineoplastic Agents, Hormonal↗

PubMed1978

Absorption and glucuronylation of diethylstilbestrol by the rat small intestine.

1. The absorption and glucuronylation of [14C]diethylstilbestrol (DES) were studied in situ in segments of rat small intestine. 2. DES glucuronide accounted for nearly 50% of the methanol-soluble radioactive material appearing in the intestinal venous blood. 3. There was no difference between DES glucuronide formation in intestinal segments near the pyloric sphincter and in segments located near the ileo-caecal junction. 4. The appearance of DES and its glucuronide in the venous blood of aborally-located segments was dose-dependent from 0.1 to 5 mM, but in orally-located segments, an increase in DES concn. from 2 to 5 mM produced no increase in DES or its glucuronide in the venous blood. In neither of these intestinal regions was the rate of appearance of DES or DES glucuronide dependent upon intestinal blood flow. 5. The results indicate that intestinal glucuronylation of certain compounds during absorption may be significant over a wide range of concn. in all regions of the intestine.

Absorption↗

PubMed1993

Effects of diethylstilbestrol (DES) medication during pregnancy: report from a symposium at the 10th international congress of ISPOG.

This article is a report based on presentations at the symposium Effects of Diethylstilbestrol (DES) Medication during Pregnancy at the conference Reproductive Life, 10th International Congress of The International Society of Psychosomatic Obstetrics and Gynaecology (ISPOG) in Stockholm, Sweden June 14-17, 1992. The objective of this symposium, chaired by Eylard van Hall and Ingar Palmlund, was to provide the basis for a discussion of how the risks of DES had been evaluated in different countries. In the general discussion following the presentations everybody present expressed concerns that DES might still be given to pregnant women in many parts of the world, called for measures to alert medical professionals world-wide to the hazards of the use of DES, and requested measures to effect an international ban of DES in medication for pregnant women.

Abnormalities, Drug-Induced↗

PubMed1996

Exposure to a xenoestrogen before birth: the diethylstilbestrol experience.

The experiences of diethylstilbestrol (DES), used as a medication for pregnant women, provide a panorama of the effects of an elevated exposure to xenoestrogens during the development of a fetus. DES was common as pregnancy medication in North America, and several European countries from the 1950s into the 1970s. It may still be prescribed as pregnancy medication in Third World countries. DES exposure in utero has been shown to have carcinogenic, teratogenic and reproductive effects. The medical community needs to be alerted to appropriate treatment of patients exposed in utero to elevated levels of estrogens.

Adult↗

PubMed1978

Spectra of glutamate dehydrogenase with diethylstilbestrol.

Glutamate dehydrogenase displays hyperchromicity at 256 nm and at 276 nm upon binding of diethylstilbestrol. Increase in absorbancy is linear at both regions up to 250 micrometer DES, and becomes parabolic at higher concentration of DES. ADP in the presence of DES causes decrease in absorbancy at 256 nm; absorbancy at 276 nm increased by DES is not affected by ADP. DES prevents spectral effects produced by GTP (decrease in absorbancy at 254 nm and at 276 nm). ADP still decreases absorbancy at 254 nm, leaving the 276 nm region unchanged. ADP enhances spectral effects produced by GTP. GTP, however, prevents changes produced by ADP.

Adenosine Diphosphate↗

PubMed1986

Development of vaginal adenosis-like lesions and uterine epithelial stratification in mice exposed perinatally to diethylstilbestrol.

Pregnant ICR/JCL mice were given either four daily subcutaneous injections of 20-2000 micrograms diethylstilbestrol (DES)/day or a 4-day intravenous infusion of 20-200 micrograms DES/day starting on Day 15 of gestation. Female mice were injected with 0.01-50 micrograms DES/day for 5 days starting on the day of birth. Females given oil injections during the neonatal period and offspring of mothers given injections of an infusion of respective vehicles alone served as controls when corresponding ages were attained. Incidence of adenosis-like lesions (ADL) in the vaginal epithelium and stratification of the uterine epithelium (UST) were determined in both offspring and neonatally exposed mice at 30 days of age. Injections of 0.1-50 micrograms DES/day during the neonatal period induced ADL in the fornical epithelium of vagina (36-70%), but not UST. A high incidence of ADL (80-88%) was found in the fornical and upper-vaginal epithelia in offspring of mothers given injections of 200-2000 micrograms DES/day, and UST was encountered in 38-70% of these mice. Offspring of mothers given an infusion of 20 micrograms DES/day had low incidences of ADL (11%) and UST (22%), whereas offspring of mothers infused with 200 micrograms DES/day exhibited high incidences of ADL (71%) and UST (86%). In offspring of mothers given injections of 2000 micrograms DES/day, ADL appeared in the fornical and upper-vaginal epithelial as early as 15 days of age. Thus, the present study revealed that ADL and UST occur at a high incidence in infantile mice exposed prenatally to high doses of DES. Previous studies failed to detect such effects perhaps due to the strain of mice, methods, duration, and/or dose of DES used.

Animals↗

PubMed1986

Blood flow in diethylstilbestrol-induced anterior pituitary gland hyperplasia.

Anterior pituitary hyperplasia was developed in female Fisher 344 rats by subcutaneously implanted slow-release diethylstilbestrol (DES) capsules. Blood flow was measured in two separate areas of the adenohypophysis using hydrogen clearance method at 6, 9, 10, and 13 weeks after the implantation. Blood flow progressively decreased while the DES capsules were in place (normal values in ml/g/min, mean +/- SD: 0.93 +/- .12 laterally and 1.15 +/- .11 medially, decreasing to 0.25 +/- .07 and 0.24 +/- .07, respectively, by 13 weeks). Histology confirmed nodular hyperplasia, development of large vascular lakes, and hemorrhages within the adenohypophysis. Total adenohypophysial blood flow was calculated as a product of mean blood flow as measured per unit weight and the weight of the gland. This figure progressively increased from 12.7 +/- 2 to 22.2 +/- 8 microliter/min by 13 weeks. All these changes were significant at the P less than 0.001 level. These blood flow measurements suggest that the hyperplastic adenohypophysis outgrows its blood supply which is additionally compromised by "useless" pooling of blood in the vascular lakes. However, there is an overall increase in the amount of blood flowing through the hyperplastic gland which may be explained by newly formed supplying vessels.

Animals↗

PubMed1987

The relative binding affinity of diethylstilbestrol to uterine nuclear estrogen receptor: effect of serum and serum albumin.

The relative binding affinity (RBA) of diethylstilbestrol (DES) was determined in nuclear fractions of the rat uterus. DES displayed a two- to threefold greater affinity (RBA = 245 +/- 36) than estradiol (RBA = 100) for nuclear E receptor. The RBA of DES to nuclear E receptor was lowered significantly in the presence of rat serum (43 +/- 1) or human serum (52 +/- 7). Dilution of human serum resulted in a progressive increase in the RBA of DES which approached that observed in the absence of serum. Addition of purified human serum albumin mimicked the decrease in RBA of DES that was observed with serum. The IC50 of estradiol was not changed in the presence of either rat serum or albumin. These data show that DES possesses a greater affinity for nuclear E receptor than estradiol and that serum albumin can modulate DES binding to uterine E receptor.

Animals↗

PubMed1989

Prolactin sensitivity of mammary epithelial cells from mice exposed neonatally to diethylstilbestrol.

We examined the responsiveness to prolactin and growth hormone of mammary epithelial cells from mice exposed neonatally to diethylstilbestrol (DES) and from control mice. The mammary epithelial cells were cultured inside collagen gels with serum-free medium containing insulin, epidermal growth factor, and linoleic acid. This produces prolactin-sensitive cells with low levels of casein production, as measured in cellular homogenates with a specific enzyme-linked immunosorbent assay for alpha-casein. The collagen gels containing these cells were then released and the medium supplements changed to insulin, linoleic acid, and prolactin at concentrations from 10 to 1000 ng/ml and growth hormone at 0, 10, or 100 ng/ml. This second phase of the culture, the differentiation phase, allows the cells to accumulate casein if they have this capacity. When cultured with prolactin only (no growth hormone), the cells from DES-exposed mice consistently accumulated 50-100% of the casein content of normal cells, but never more. Growth hormone, when added to prolactin-containing medium, increased casein accumulation above the levels seen with prolactin alone. Combinations of prolactin and growth hormone enhanced the difference between casein accumulation in DES-exposed and control cells, and DES-exposed cells were much less responsive to growth hormone. In our studies, the isolated mammary epithelial cells of estrogen-exposed mice are not more sensitive to prolactin than cells from normal animals as previous reports reports had suggested, but rather are generally less sensitive to hormonal stimulants.

Animals↗

PubMed1990

Effects of early exposure to diethylstilbestrol on cellular protein expression by mouse vaginal epithelium and fibromuscular wall.

Epithelia and fibromuscular walls were dissociated from the vaginae of ovariectomized BALB/cCrgl mice (ca. 41 days old) exposed neonatally to diethylstilbestrol (DES) or sesame oil and purified by centrifugation through Percoll density gradients. Neonatal exposure to DES caused the vaginal epithelium to become permanently proliferated and partially keratinized; the control epithelium was low cuboidal. The major cellular proteins expressed in each tissue compartment were examined by two-dimensional gel electrophoresis of [35S]methionine-labeled tissues. The epithelia and fibromuscular walls displayed distinctive two-dimensional protein patterns. In the DES-exposed vaginal epithelium, the expression of two proteins (one had a molecular size of 65 kDa and a pl of 6.0, and the other had a molecular size of 38 kDa and a pl of 6.3) was increased, while the expression of three proteins with molecular sizes of 25, 30, and 140 kDa and pls of 5.6, 5.6 and 6.7, respectively, was reduced, relative to the control epithelium. In the DES-exposed vaginal fibromuscular walls, the expression of 9 proteins was increased whereas the levels of 21 specific proteins, distinct from those in the epithelium, were decreased. Thus, long-term tissue-specific alterations in the synthesis of a select number of cellular proteins occur in the DES-exposed vagina.

Animals↗

PubMed1991

Effect of certain growth factors on proliferation in serum-free collagen gel culture of vaginal epithelial cells from prepuberal mice exposed neonatally to diethylstilbestrol.

Neonatal treatment with diethylstilbestrol (DES) induces ovary-independent vaginal epithelial changes in mice. The response of vaginal epithelial cells from intact prepuberal BALB/cCrgl mice treated neonatally with 2 micrograms of DES for 5 days to growth-stimulatory and -inhibitory factors was studied using a serum-free collagen gel culture system that sustains the growth of normal vaginal epithelial cells. Cells from control and DES-exposed mice at 21 days of age showed about a 5-fold increase in number during 10 days in a serum-free medium supplemented with transferrin, bovine serum albumin fraction V, insulin, and epidermal growth factor. Epidermal growth factor and insulin stimulated dose-related proliferation of vaginal epithelial cells from both control and DES-exposed mice; however, cells from DES-exposed mice showed a reduced growth response to epidermal growth factor and an increased growth response to insulin, compared with control cells. Insulin-like growth factor I (1-100 ng/ml) tested in the absence of insulin failed to stimulate cell growth. Transforming growth factor-beta (0.05-5 ng/ml) consistently inhibited cell growth in a dose-dependent manner.

Animals↗

PubMed1992

Temporal effects of estradiol and diethylstilbestrol on pituitary and plasma prolactin levels in ovariectomized Fischer 344 and Holtzman rats: a comparison of radioimmunoassay and Nb2 lymphoma cell bioassay.

An Nb2 lymphoma cell bioassay (Nb2BA) and a radioimmunoassay (RIA) were used to compare plasma and pituitary levels of prolactin in ovariectomized Fischer 344 (F344) and Holtzman rats treated with either diethylstilbestrol (DES) or estradiol for up to 8 weeks. The objectives were to determine whether there were temporal differences in prolactin responses in strains with different genetic predispositions to estrogen-induced pituitary tumor formation and to determine whether the results of the two assay methods were equivalent. All rats were ovariectomized for 7 days and all except controls received subcutaneous Silastic implants of DES or 17 beta-estradiol and were sacrificed at intervals from 2 days to 8 weeks later. Pituitary content and plasma levels of prolactin were determined by Nb2BA and RIA and the ratio of these measurements was calculated. DES induced a significant increase in pituitary prolactin in F344 rats by 2 days of treatment, as measured by RIA. Pituitary content increased to a peak by Day 4, after which a gradual decline occurred until the end of the experiment. Nb2BA measurements were similar to those obtained by RIA, except at 8 weeks, when the content determined by Nb2BA was significantly higher than the content determined by RIA. When estradiol was given to F344 rats a pattern of increase and subsequent decrease in pituitary content similar to that seen with DES was observed and levels measured by Nb2BA and RIA were essentially equivalent. Plasma levels of prolactin in DES-treated F344 rats increased exponentially through the 8 weeks, and the Nb2BA measurements were significantly greater than levels determined by RIA throughout the treatment period. Estradiol treatment produced a pattern of change in plasma levels of prolactin similar to that observed with DES, except that RIA and Nb2BA measurements were not different. Comparable results were obtained in Holtzman rats, except plasma levels were not increased to the same degree as seen in F344 rats. From these results, we conclude that DES, but not estradiol, can selectively increase the secretion of prolactin that is more bioactive than immunoreactive and that this effect of DES is observed in F344 and Holtzman rats, although F344 rats released more prolactin in response to estrogens than did Holtzman females.

Animals↗

PubMed1993

Epidermal growth factor receptor levels in reproductive organs of female mice exposed neonatally to diethylstilbestrol.

Binding of epidermal growth factor (EGF) to membrane preparations of vagina, uterus, ovary, oviduct, and liver was examined in mice treated neonatally with diethylstilbestrol (DES) and compared with that in untreated mice. Binding in the vagina (12.5 +/- 0.73 fmol/mg protein) was somewhat higher than in the uterus (8.0 +/- 0.34 fmol/mg protein). Level of specific binding was of the order: liver (18.4 +/- 1.09 and 16.0 +/- 1.53 fmol/mg protein) > vagina (12.5 +/- 0.73 and 8.2 +/- 0.57 fmol/mg protein) > uterus (8.0 +/- 0.34 and 6.8 +/- 0.56 fmol/mg protein) > ovary (6.8 +/- 0.36 and 8.0 +/- 1.05 fmol/mg protein) > oviduct (2.1 +/- 0.32 and 1.7 +/- 0.05 fmol/mg protein) in control and neonatally DES-exposed mice, respectively. Thus, neonatal DES exposure significantly lowered the binding site level only in the vagina, without modifying the binding affinity (Kd = 5.4 x 10(-9) M in controls vs 4.6 x 10(-9) M in DES-exposed mice). Reduction of EGF receptor level in the vagina correlates with ovary-independent persistent proliferation and keratinization of the vagina induced by neonatal DES exposure. EGF receptors were immunohistochemically demonstrated in epithelial cells of vagina, uterus, and oviduct and in stromal cells in uterus and oviduct using a polyclonal antibody to human EGF receptor protein.

Animals↗

PubMed1995

Dynamics of prolactin secretion from diethylstilbestrol-induced rat prolactinoma tissue in vitro.

Experiments were performed to determine whether PRL secretion in the rat diethylstilbestrol (DES)-induced prolactinoma model is affected by the addition of thyrotropin-releasing hormone (TRH) and/or immunoneutralization of intrapituitary vasoactive intestinal polypeptide (VIP) in vitro. Male Fischer 344 rats were implanted with either a 10 mg DES or placebo pellet 30 days prior to obtaining the anterior pituitary glands for perifusion. The anterior pituitaries were quartered and used in three different perifusion experiments. In Experiment I, placebo-treated tissue channels were perifused for 2 baseline hr followed consecutively by a 30-min exposure to 1:100 nonimmune rabbit serum (NRS), a 30-min wash, and a final 30-min exposure to 10(-5) M TRH. Additional placebo channels were run as above except 1:100 VIP antiserum (AVIP) was substituted for NRS and AVIP was added to the TRH. In Experiment II, the same perifusion protocol was used as in Experiment I, except DES-induced tumor tissue was used instead of placebo tissue. Results from Experiment I and II reveal that AVIP significantly decreased PRL secretory rate in both DES and placebo groups. In the tumor group, both TRH alone and in the presence of AVIP significantly increased the PRL secretory rate. In Experiment III DES-induced tumor tissue channels were perifused with a similar protocol, except the concentrations of NRS and AVIP were increased to 1:10. Both NRS and AVIP significantly decreased PRL secretory rate; however, AVIP had a significantly greater effect than NRS. In this experiment, 1:10 AVIP overcame the stimulatory effect of TRH. In conclusion, AVIP decreases and TRH increases, even in the presence of AVIP, PRL release in DES-induced prolactinoma tissue in vitro. Increasing the AVIP concentration 10-fold diminished the PRL-releasing action of TRH in the tumor tissue. These data suggested that PRL secretion is not autonomous in these prolactinomas and can be affected by exogenous TRH and partial immunoneutralization of endogenous VIP.

Animals↗