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PubMed1985

The effect of long-term diethylstilbestrol treatment or hyperprolactinemia on the response of the tuberoinfundibular dopamine neurons to elevated prolactin.

Adult male rats were rendered hyperprolactinemic by two different methods. Some animals received subcutaneous implants of diethylstilbestrol (DES) or empty capsules. After 2 months the capsules were removed. Other rats received 3 anterior pituitary homografts under the kidney capsule or had sham surgery. The DES-treated rats were killed 8 months after capsule removal, while pituitary-grafted rats were killed 4 or 12 months after surgery. The DES-treated rats had hyperplastic anterior pituitaries, and both the DES-treated rats and the rats with anterior pituitary homografts were hyperprolactinemic. The activity of the TIDA neurons, as evidenced by dopamine (DA) synthesis in the median eminence (ME), was markedly and comparably elevated in both of these experimental groups of rats when compared to their respective controls. These data: show that the maintenance of hyperplastic pituitaries 8 months after DES withdrawal is not due to impaired function of the TIDA neurons; and provide no evidence for a neurotoxic effect of prolonged hyperprolactinemia on the response of the TIDA neurons to elevated PRL.

Animals↗

PubMed1987

Effect of chronic hyperprolactinemia on tuberoinfundibular dopaminergic neurons: histofluorescence in aged and in diethylstilbestrol-treated male rats.

Catecholamine histofluorescence was used to examine morphology of hypothalamic tuberoinfundibular dopaminergic (TIDA) median eminence-afferent neurons (areas A12 and A14) in male Fischer 344 rats bearing prolactin (PRL)-secreting tumors. These tumors were either spontaneous, discovered in rats aged 20-32 months, or were induced by chronic diethylstilbestrol (DES) treatment in younger animals. In the latter case, histofluorescence was examined in two groups of animals: (1) those which had been treated, beginning at 6 months of age, with 8 weeks of DES, and subsequently had had the treatment discontinued for 10 months, but which continued to exhibit hyperprolactinemia; (2) animals treated continuously with DES, for 50 or 70 days. Histofluorescence was induced using either the Falck-Hillarp, aluminum-formaldehyde ('ALFA') or the formaldehyde-glutaraldehyde ('FAGLU') technique and pituitaries were examined for PRL immunoreactivity, as permitted by the fixation method chosen for histofluorescence. For selected animals, pituitaries were enzymatically dissociated, maintained in primary culture, and were assessed for PRL cell quantification, intracellular PRL content, and in vitro release. Among animals treated chronically with DES, histofluorescence was assessed by the Falck-Hillarp technique, and counts of A12 and A14 perikarya were made in each hypothalamus. Median eminence zona externa fluorescence was diminished in aged rats with normal pituitaries, in aged rats bearing spontaneous tumors, and in rats treated continuously with DES, in comparison with fluorescence in younger rats with normal pituitaries or from which DES treatment had been with-drawn. Perikaryal fluorescence showed typical cell morphology and numbers in aged rats, aged rats bearing spontaneous tumors, and in rats from which DES had been withdrawn. In one animal, treated continuously for 70 days with DES, numbers of A12 and A14 perikarya decreased. In aged rats bearing spontaneous tumors, histofluorescence morphology indicated stimulatory effects on TIDA perikarya and terminals, including increased perikaryal and terminal fluorescence intensity. The morphological results support biochemical evidence of PRL stimulation of tuberoinfundibular dopaminergic neurons, and suggest that inhibitory effects of increased PRL secretion on these hypothalamic cells in DES-induced hyperprolactinemia reflect a direct and reversible effect of DES on these neurons.

Aging↗

PubMed1988

Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment.

The volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the male rat brain is larger than that of the female. In the female rat, treatment with diethylstilbestrol (DES), either perinatally (from day 16 of gestation to postnatal day 10), or postnatally (birth to day 10) was equally effective in increasing the volume of SDN-POA compared to controls. Prenatal treatment (day 16 of gestation to birth) with DES also increased the volume of the SDN-POA but this increase was significantly smaller than that achieved with the other treatments. These results confirm the effectiveness of DES in increasing the volume of the SDN-POA in the female rat brain, and prove that the differentiating SDN-POA is very receptive to hormone influences in the early postnatal period.

Aging↗

PubMed1986

Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: a model of aberrant macrophage development.

Administration of the synthetic estrogen diethylstilbestrol (DES) lowers the systemic resistance of mice to challenge with either tumor cells or the facultative intracellular parasite Listeria monocytogenes. To assess the potential role of impaired mononuclear phagocyte system (MPS) function in this depression of host resistance, we addressed the question of systemic perturbations of the MPS induced by administration of DES. A panel of objective quantitative markers which have been previously shown to identify and characterize macrophages in the several stages of development of activation was employed. DES perturbed the resident population of peritoneal macrophages by increasing their number approximately twofold and by enhancing their competence for phagocytosis, cytostasis of tumor cells, and secretion of plasminogen activator. When we examined the competence of the MPS in DES-treated mice to respond to challenge with activating stimuli, we found that DES systemically suppressed the development of macrophages, in response to either pyran copolymer or BCG, to develop tumoricidal function and to gain competence for secretion of reactive oxygen intermediates such as H2O2. Since these data suggested that DES inhibited the development of macrophages from a precursor stage (i.e., responsive macrophages) to activated macrophages in vivo, we tested this possibility directly by applying known activating signals in vitro to responsive macrophages. Responsive macrophages from DES-treated mice did not become activated in response to the application of two known potent activating signals (i.e., MAF + LPS). Taken together, the data indicate that DES systemically perturbs the MPS and does so by enhancing development of the early stages of maturation and suppressing subsequent development.

Animals↗

PubMed1984

Peroxidase-mediated binding of diethylstilbestrol analogs to DNA in vitro: a possible role for a phenoxy radical.

In order to investigate the role of peroxidase-mediated metabolic activation in the mechanism of carcinogenicity of diethylstilbestrol (DES), a series of 14C-labelled analogs of DES was synthesized and their binding to DNA upon oxidation by peroxidases from horseradish or mouse uterus was studied in vitro. The compounds chosen for this study were the erythro and threo form of hexestrol (HES), the E,E- and Z,Z-isomer of dienestrol (DIES) and the mono- and dimethyl ether of DES. Non-extractable binding to DNA was observed for all compounds with at least one free hydroxyl group independent of the stilbene structure. The extent of binding was highest for the HES isomers and for E,E-DIES, whereas Z,Z-DIES and the monomethyl ether were bound to about the extent of DES. These findings imply that the formation of a phenoxy free radical is sufficient for non-extractable DNA binding and the stilbene structure is not required for peroxidase-mediated activation of DES.

Animals↗

PubMed1985

Nature of the macromolecular binding of diethylstilbestrol to DNA and protein following oxidation by peroxidase/hydrogen peroxide.

Incubation of [14C]diethylstilbestrol ([14C]DES) with horseradish peroxidase(HRP)/hydrogen peroxide in the presence of various polynucleotides and proteins led to macromolecular binding of radioactivity. Binding to DNA proved stable against ethanol precipitation, but was completely removed when the DNA was subjected to gel electrophoresis, caesium chloride density centrifugation, and mild hydrolysis. In contrast, binding to protein was stable in gel electrophoresis. The extent of binding did not differ significantly between proteins with and without thiol groups. These results imply that the products of peroxidase-mediated oxidation of DES bind to DNA in a strong but non-covalent manner, whereas binding to protein appears to be covalent and does not depend on the presence of thiol groups. The possible nature of the binding species is discussed.

Carbon Radioisotopes↗

PubMed1985

Oxidative and conjugative metabolism of diethylstilbestrol by rabbit preimplantation embryos.

Five- and six-day-old rabbit preimplantation embryos were found to be capable of metabolizing [3H]diethylstilbestrol (DES) in vitro. Based on the analysis of the metabolites formed during a 24-hr incubation period we conclude that these early stage embryos do have active monooxygenase and conjugative activity. The monooxygenase seems to be specific to this early stage of embryonic development.

Animals↗

PubMed1990

Quantitative change in fibronectin in cultured müllerian mesenchymal cells in response to diethylstilbestrol and müllerian-inhibiting substance.

I report on the synthesis of fibronectin in the developing chick Müllerian duct mesenchymal cells. Before the differentiation of female chick Müllerian duct, the amount of fibronectin in the cells of the right duct is 44% lower than in the left duct. While after differentiation, the amount of fibronectin in the right duct is 29% lower, as compared to the left duct. Estrogenic hormone diethylstilbestrol (DES) treatment was carried out at the 5th day of incubation when both female Müllerian ducts were undifferentiated. Three days after DES treatment, the regression of the right duct was prevented, and the amount of fibronectin was induced by 89%, while induction in the left duct was 11%. Eight days after DES administration, the amount of fibronectin in the right and left Müllerian duct was induced by 150 and 76%, respectively. After DES treatment in the male embryo, both Müllerian ducts were retained, and the capacity for fibronectin synthesis was preserved. Application of the indirect immunocytochemical labeling technique revealed Müllerian-inhibiting substance (MIS) binding sites on the membrane of the Müllerian mesenchymal cells. The addition of chick MIS in the culture medium reduced the amount of detectable fibronectin in the cultured mesenchymal cells. The synthesis of fibronectin in intestinal mesenchymal cells was not affected by DES or MIS.

Animals↗

PubMed1988

Effects of diethylstilbestrol exposure in utero on the genital tracts of female ACI rats.

Aspects of development and morphology were studied in the reproductive tract of female ACI rats exposed prenatally to diethylstilbestrol (DES) and followed to 10 months of age. Pregnant ACI rats were injected with vehicle or DES (0.8 microgram = low DES or 8.0 micrograms = high DES) on Days 15 and 18 of gestation. At 12 weeks of age, half of the female offspring in each prenatal exposure group received a subcutaneous implant of a pellet containing 2.5 mg DES and 17.5 mg cholesterol; the remaining offspring received a control cholesterol pellet. Maternal reproductive performance was significantly impaired in DES-treated dams compared to controls. In female offspring mean time of vaginal opening was accelerated from 50.3 +/- 2.7 days in the vehicle-exposed group to 46.2 +/- 2.6 and 47.1 +/- 2.3 days in the low and high DES groups, respectively. Prior to pellet implantation, none of the rats exposed to DES prenatally was in "persistent estrus." At necropsy, rats exposed to DES in utero and implanted with the cholesterol pellet showed an increased frequency of atypical uterine epithelia, cystically dilated uterine glands, and a thickened vaginal epithelium. Among groups implanted with the DES pellet, prenatal exposure to DES increased the incidence of squamous metaplasia of the luminal epithelium and of cystically dilated uterine glands. Collectively, groups implanted with the DES pellet had higher incidences of squamous metaplasia of the uterine lumen, cystically dilated uterine glands, and patches of multilayered uterine epithelium than groups bearing the cholesterol pellet. DES pellet-bearing rats were also found to display a pronounced thickening and vacuolation of the vaginal epithelium. Cervical tissue from 98% of the DES-treated litters was characterized by a markedly convoluted epithelium with numerous squamous cell nests. There were no apparent effects of prenatal DES exposure or postnatal DES treatment on ovarian or oviductal histology. However, ovarian wet weights were significantly reduced as a result of postnatal DES treatment. Thus, the epithelial tissues of the uterus, cervix, and vagina in the ACI rat show a sensitivity to DES whether administered prenatally, postnatally, or in combination.

Animals↗

PubMed1988

Inhibition of the H+-ATPase in bovine adrenal chromaffin granule ghosts by diethylstilbestrol. Evidence for a tight coupling between ATP hydrolysis and proton translocation.

Diethylstilbestrol (DES) was found to inhibit reversibly the hydrolysis of MgATP (80% at 100 microM) and proton pump activity (I50 approximately equal to 15 microM, complete at 100 microM) in chromaffin granule ghosts. The parallel inhibition suggests a tight kinetic coupling between the two activities. The Mg2+-ATPase activity, but not proton pumping, was partially restored by N,N'-dicyclohexylcarbodiimide, indicating that the two inhibitors in combination cause a partial uncoupling. The non-competitive type of inhibition shows that the action of DES is distal to the site of ATP binding and hydrolysis. Although unspecific, the interaction of DES with the chromaffin granule membrane seems primarily to affect the H+-ATPase.

Adenosine Triphosphate↗

PubMed1984

Psychosexual milestones in women prenatally exposed to diethylstilbestrol.

Thirty women aged 17 to 30 years with a record-confirmed history of prenatal exposure to diethylstilbestrol (DES) were compared to 30 women of similar age and demographic background with a history of abnormal Pap smear findings. Heterosocial and heterosexual histories were assessed by systematic semistructured interviews. The groups differed neither in the age at menarche nor in the age at attainment of various psychosexual milestones.

Adolescent↗

PubMed1987

Estrogenic contributions to sexual differentiation in the female guinea pig: influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development.

We administered the synthetic estrogen, diethylstilbestrol (DES), or the antiestrogen, tamoxifen, to pregnant guinea pigs and observed the consequences for sexual differentiation of their female offspring. Hormones were administered during the period when treatment of fetuses with testosterone influences the development of sex-related traits (approximately Days 30 to 65 of gestation). Ovarian function, masculine and feminine sexual behavior, and the structure of a sexually dimorphic neural region in the preoptic area were assessed in adulthood in hormone-exposed animals and in oil-treated and untreated controls. Prenatal exposure to DES dipropionate (DESDP) caused masculinization and defeminization. DESDP-treated females mounted more than control females, both without hormonal stimulation and when given testosterone propionate (TP) as adults. The sexually dimorphic neural region was also masculinized in these females. In regard to defeminization, they showed delayed vaginal opening, impaired progesterone (P) production, an absence of corpora lutea, and impaired lordosis and mounting responses to estradiol benzoate (EB) and P. Prenatal treatment with tamoxifen produced a complicated pattern of results. Tamoxifen-exposed females evidenced less masculine-typical behavior, showing diminished mounting without hormonal stimulation and in response to TP. However, they also showed delayed vaginal opening, enhanced P production, and impaired mounting in response to EB and P. Their lordosis behavior and the volume of the sexually dimorphic neural region were unaffected. These results suggest that estrogens play a substantial role in sexual differentiation in the guinea pig. High levels of estrogen promote masculine-typical development, and unusually low levels may impair some aspects of both masculine-typical and feminine-typical development.

Animals↗

PubMed1989

The development of gender-related behavior in females following prenatal exposure to diethylstilbestrol (DES).

Animal research has shown that diethylstilbestrol (DES) present during the sensitive developmental periods of the hypothalamus and adjacent areas of the brain affects the development of sex-dimorphic brain structures and subsequent behavior. To test for corresponding behavioral effects in humans, 30 women with a history of prenatal DES exposure were contrasted with 30 unexposed women who had been referred to the same clinic for a colposcopic examination because of an abnormal Pap smear. Gender-role behavior of childhood, adolescence, and adulthood was assessed by means of a semistructured interview, the Gender Role Assessment Schedule-Adult, and the Bem Sex Role Inventory. The mothers of these women were interviewed about their daughters with the "mother form" of the same interview schedule. The results suggest that DES women show less orientation toward parenting than the controls. There were no consistent group differences in other domains of gender-role behavior.

Adolescent↗

PubMed1992

Prenatal diethylstilbestrol exposure and performance on college entrance examinations.

The fetal rodent brain is permanently altered by exposure to sex hormones. Long-term effects of prenatal sex hormones on the human brain are far less clear. In order to explore such effects, we studied a measure of cognitive function among young adults who had been exposed in utero to a powerful synthetic estrogen. In a randomized clinical trial conducted at the University of Chicago in 1950-1952, 1646 pregnant women were randomly assigned to receive either high doses of diethylstilbestrol or placebo. Women in this study gave birth to 1653 liveborn infants, of whom 1603 (820 sons and 783 daughters) survived to their fifteenth birthday. College entrance examination scores were obtained for 42% of these offspring. No differences in test performance were seen among exposed daughters. Among sons, test scores were marginally higher among the exposed, probably due to chance.

Adult↗

PubMed1992

Effects of prenatal exposure to diethylstilbestrol (DES) on hemispheric laterality and spatial ability in human males.

Ten males exposed to diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, during gestation were compared to their matched, unexposed brothers on measures of brain hemispheric specialization for processing nonlinguistic spatial information and cognitive abilities. DES exposure was associated with reduced hemispheric laterality and lowered spatial ability. These data provide direct evidence of a relationship between brain laterality, spatial cognitive ability, and prenatal exposure to hormones in human males. Further, the implications of these findings for understanding sexual differentiation of the human brain are discussed.

Adolescent↗

PubMed1978

Relation of hemodynamics to the incidence of diethylstilbestrol-induced aortic ruptures in hypertensive and hypotensive lines of turkeys.

Hypertensive and hypotensive lines of turkeys were treated with diethylstilbestrol (DES) alone, or with DES and propranolol (PROP). Untreated turkeys of each blood pressure line served as controls. Mortality rate from aortic ruptures was highest (43.7%) in the hypertensive line treated with DES, but mortality was reduced to 7.7% when this line of turkey was treated with both DES and PROP. Among the hypotensive line of turkeys treated with DES, 26.7% died of aortic ruptures, but none died when these turkeys were treated with DES and PROP. Propranolol did not influence serum cholesterol levels, and all DES or DES and PROP treated birds had greatly elevated values, as contrasted to untreated turkeys. Aortic lipid values were highest in the hypotensive line of turkeys treated with DES, but, by histologic evaluation, aortic atherosclerosis was equally severe in all DES-treated turkeys. Blood pressure and aortic dp/dt max were higher in the hypertensive line treated with DES than in the similarly treated hypotensive line. This probably accounted for the higher mortality in the former group. Absence of significant mortality in either line of turkey following treatment with both DES and PROP apparently resulted from the decreased stress on the aorta caused by lowering of blood pressure and aortic dp/dt max by PROP.

Animals↗

PubMed1985

Evidence of improved pregnancy outcome with diethylstilbestrol (DES) treatment of women with previous pregnancy failures: a retrospective analysis.

In a longitudinal study of 2378 pregnancies, diethylstilbestrol (DES) therapy was associated with an increased live-birth rate in patients with a history of prior pregnancy wastage. The data were analyzed statistically by comparing the rates of success with and without DES treatment in pregnancies grouped according to similar reproductive histories. The effect of DES on the outcome of pregnancy has not been assessed previously in this manner.

Abortion, Threatened↗

PubMed1982

Binding and retention of estrogen in the uterus of hamsters treated neonatally with diethylstilbestrol.

We have shown previously that postpubertal estrogen exposure promotes the development of uterine tumors in hamsters treated neonatally with diethylstilbestrol (DES). The purpose of this study was to determine if the uterine estrogen receptor system of adult hamsters was altered after neonatal DES treatment. There was no effect on the concentration, subcellular distribution, apparent binding affinity, sedimentation properties, surface charge characteristics or ligand specificity of uterine estrogen receptor in ovariectomized, estrogen-replaced animals. Furthermore, neonatal DES treatment had no effect on the subcellular distribution of radioactivity in the uterus of adult animals ovariectomized 1 week before challenge with [3H]-estradiol-17 beta (E2). However, the amount of radioactivity taken up and specifically bound within the uterus 6 h after [3H]-E2 challenge was less in DES-treated compared to control animals. Six hours after challenge with unlabeled E2, the concentration (pmol/g tissue) of occupied but not total nuclear estrogen receptor was reduced in DES-treated animals. The difference in uterine radioactivity levels and occupied nuclear receptor retention appears to be due to a difference in estrogen metabolism since the systemic concentration of authentic [3H]-E2 was lower in DES-treated animals compared to control. These results demonstrate no DES-induced change in the physicochemical or functional properties of the uterine estrogen receptor system, suggesting that a lesion in this receptor system is not involved in the etiology of uterine tumor development following neonatal DES exposure. However, the DES-treated animal appears to have an enhanced estrogen metabolism.

Animals↗