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PubMed1987

Depression and diethylstilbestrol exposure in women.

Fifty women exposed to diethylstilbestrol (DES) in utero, 50 of their unexposed sisters (sister controls) and 43 women with abnormal Papanicolaou smears (population controls) were tested using the Diagnostic Interview Schedule to assess differences in depression and other kinds of psychologic impairment possibly associated with DES exposure. There were significant differences between DES-exposed women and their sisters in major depression and major recurrent depression. Papanicolaou controls were more depressed in comparison to sister controls. However, there were no significant differences in depression between Papanicolaou controls and the DES exposed, suggesting that major and recurrent depressions are more likely to result from concern about reproductive and other gynecologic problems than from the hormonal effects of intrauterine exposure to DES. Differences in amphetamine abuse/dependence were also noted between the DES exposed and the sister controls.

Adolescent↗
PubMed1986

Effect of prenatal and/or neonatal diethylstilbestrol (DES) or allylestrenol (AE) treatment on the postnatal development of the chicken ovary.

Chickens treated with allylestrenol or diethylstilbestrol in the egg on 9th day of incubation, or one day after hatching, or on both occasions, equally showed histomorphological indications of a distinct ovarian activation at 5 days of age, which was most pronounced in the twice-treated birds. A single steroid exposure at one day of age accounted for inhibition of ovarian activity at 6 weeks, presumably owing to a long-term effect on the hypothalamo-hypophyseal system, which begins to function from the 12th day of incubation.

Allylestrenol↗
PubMed1987

Effects of diethylstilbestrol and propylthiouracil on the rat pituitary. An immunohistochemical and ultrastructural study.

The effects of diethylstilbestrol [(DES) CAS: 56-53-1] and propylthiouracil [(PTU) CAS: 51-52-5] on the pituitary glands of female weanling F344 rats were studied by immunohistochemistry and electron microscopy. Six weeks of PTU treatment resulted in a significant increase in pituitary gland weight and in the percentage of pituitary prolactin (PRL) cells. The percentage of thyroid-stimulating hormone (TSH) cells was slightly increased in PTU-treated rats. DES treatment produced a thirteenfold increase in pituitary gland weight and a significant increase in the percentage of PRL cells as well as in serum PRL levels. Combined PTU-DES treatment increased pituitary gland weight and serum PRL levels, but this increase was less than that observed with only DES treatment. A relative decrease in the percentage of TSH cells was seen after both DES and PTU-DES treatment. Ultrastructural immunohistochemical studies showed two types of PRL cells in the pituitary of all groups. Classical PRL cells with granule diameters of 150-800 nm were most abundant in DES-treated groups, whereas cells with smaller granules, 100-350 nm in diameter, were equally prominent in control groups and after PTU treatment. The results of this study show that while PTU causes a slight increase in pituitary gland weight and in PRL cell numbers, it inhibits estrogen-induced PRL cell hyperplasia. This model can be used to study the effects of PTU on pituitary PRL cell morphology and on the regulation of PRL cell hyperplasia.

Animals↗
PubMed1987

The effects in the human of diethylstilbestrol (DES) use during pregnancy.

Intrauterine diethylstilbestrol (DES) exposure is associated with an increased risk for the development of clear cell adenocarcinoma (CCA) of the vagina and cervix. The age of the patients at diagnosis has varied from 7-35 years with the highest frequency from 14-22 years. The risk among the exposed, however, is small and is of the order of 1 per 1,000. Almost all of the cases occur in postmenarchal females. Other factors that may increase the risk are maternal history of prior miscarriage, exposure to DES in early gestation, a fall season of birth and prematurity. The occurrence of CCA has paralleled the sales of DES for pregnancy support in the U.S. Both vaginal adenosis (benign glands in the vagina) and CCA are more frequent among those whose mothers began DES in early pregnancy. An increased risk of squamous cell neoplasia has been hypothesized but not proven. The changes that occur in the female genital tract of the DES exposed appear to result from alterations in the development of the mullerian ducts. Currently there is not definitive evidence for an elevated risk of cancer among DES mothers or DES sons but studies have suggested a possible increase of breast cancer in the former group and testicular cancer in the latter group; a valid association has not been established in either.

Adenocarcinoma↗
PubMed1986

Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: a Southeastern Cancer Study Group trial.

In a randomized study 115 postmenopausal women with advanced breast cancer who were estrogen receptor-unknown or -positive were treated initially with tamoxifen or diethylstilbestrol (DES). Their pretreatment characteristics showed no significant difference. The frequency of response was identical with tamoxifen and DES, showing a complete response rate of 2% versus 2% and a partial response rate of 4% versus 8%, respectively; stable disease was present in 78% versus 73% of the patients, respectively. The median time to disease progression (5 vs 6 months) and median survival depending on initial hormone therapy (34 vs 35 months) were identical for tamoxifen and DES, respectively. Gastrointestinal toxicity was more frequent and more severe with DES than tamoxifen. Responses were seen with withdrawal of each agent and on crossover to the alternative agent. Our conclusions are that: DES and tamoxifen are equally effective in treating metastatic breast cancer in the postmenopausal patient who is estrogen receptor-positive or -unknown; withdrawal and crossover responses are seen with both agents; side effects are minimal but more frequent with DES; and on the basis of cost-effectiveness DES is the preferable agent.

Adult↗
PubMed1987

Psychosis and prenatal exposure to diethylstilbestrol.

Over the past 10 years, increasing evidence has demonstrated mammalian brain development to be influenced by prenatal exposure to sex hormones. It seems possible that human behavioral abnormalities may be associated with prenatal exposure to diethylstilbestrol (DES). Relevant basic science and clinical reports are reviewed and four case reports of psychotic patients who were prenatally exposed to DES are presented.

Adult↗
PubMed1987

Diethylstilbestrol-related clear-cell adenocarcinoma in women with initial examinations demonstrating no malignant disease.

The DES Screening Center of Queens, Nassau, and Suffolk counties has screened approximately 2000 diethylstilbestrol (DES)-exposed women since its inception in 1979. Four women, who at their initial visit were noted to have only nonmalignant DES-related changes, subsequently developed clear-cell adenocarcinoma while under observation, between 18-81 months after their first colposcopy. The age at diagnosis ranged from 16-31. Three patients had been receiving close follow-up; one had not. These cases emphasize the need for frequent follow-up for these patients using careful inspection and palpation, vaginal and cervical cytology, colposcopy, and colposcopically directed biopsy of suspicious areas.

Adenocarcinoma↗
PubMedDate not supplied

Effect of centchroman on the genital organs of the offspring of rats when administered during lactation or during the neonatal period: a comparative study with ethynylestradiol and diethylstilbestrol.

Lactating rats were treated with centchroman (1.25 mg/kg body wt. p.o.) or ethynylestradiol (100 micrograms/kg p.o.) daily from day 1 of parturition for 21 days and their offspring were autopsied at 60, 90 and 120 days of age. In the offspring nursed by centchroman treated mothers there was no change in ovarian weight. There was a reduction in their uterine weight; while the luminal epithelium presented a stimulated state, the stroma showed immature state in its histological features. The ovarian and uterine weights and their histology in the offspring of ethynylestradiol treated mothers showed no change. The male offspring of both the groups of rats showed an increase in the weight of genital organs and testis histology presented typical adult features. When centchroman was injected s.c. on 5th postnatal day to female rats (500 micrograms/rat), the ovary remained normal but the uterus revealed estrogen deficient state when they were 60 or 90 days old. Neonatal female rats injected with diethylstilbestrol (10 micrograms/rat) on day 5 showed normal ovary while uterus presented features typical of estrogenic stimulation with small areas of luminal epithelium showing squamous metaplastic changes. The results are discussed comparing the centchroman effects with the reported findings in rats treated with steroidal and triphenylethylene estrogenic compounds during lactation or the neonatal period.

Age Factors↗
PubMed1987

Long-term alterations in histology and steroid receptor levels of the genital tract and mammary gland following neonatal exposure of female BALB/cCrgl mice to various doses of diethylstilbestrol.

The relation of the dosage of diethylstilbestrol (DES) administered neonatally to the incidence and severity of genital tract and mammary gland lesions and to the levels of sex hormone receptors was examined using a mouse model for human intrauterine DES exposure. Female BALB/cCrgl mice received various doses of DES (ranging from 5 X 10(-1)-10(-5) micrograms daily for the first 5 days of life) or the sesame oil vehicle alone. In the vagina, at all ages examined (1, 2, 6, and 12 months) cytosolic estrogen receptors are consistently decreased after high doses of neonatal DES (10(-1) and 1 microgram). In contrast, at the same ages, vaginal cytosolic progestin receptors increase after identical doses. In the uterus, the 1-microgram dose of neonatal DES also consistently decreases cytosolic estrogen receptors while increasing cytosolic progestin receptors at 1, 2, and 6 months of age. Histologically, neonatal doses of 5 X 10(-2) micrograms DES result in vaginal lesions at 2 months. With age, this threshold level decreases, implying interaction with an altered hormonal milieu. The uterus shows a sensitivity similar to that of the vagina in regard to the histopathological effects of neonatal DES. The ovary and mammary glands are 10- to 100-fold more sensitive to neonatal DES exposure.

Age Factors↗
PubMed1987

Transplacental effects of diethylstilbestrol on mammary development and tumorigenesis in female ACI rats.

Female ACI rats were exposed to diethylstilbestrol (DES) transplacentally and followed to 10 months of age to assess the effect of the drug on mammary development and tumorigenesis. Pregnant rats were given injections of vehicle (sesame oil) or DES (total dose, 0.8 micrograms = low DES or 8.0 micrograms = high DES) on days 15 and 18 of gestation. Pellets containing 2.5 mg DES + 17.5 mg cholesterol (DES pellet) or 20 mg cholesterol (chol pellet) were implanted s.c. into 12-week-old female offspring, creating 6 experimental groups: vehicle exposure + chol pellet (1) or + DES pellet (2); low DES exposure + chol pellet (3) or + DES pellet (4); high DES exposure + chol pellet (5) or + DES pellet (6). At sacrifice, representative mammary tissue and all palpable mammary tumors were removed for histopathological analysis. Each of the 6 experimental groups contained a minimum of 32 rats from at least 14 litters. In computation of data, the unit of analysis was the litter. Groups which had received any DES (prenatally or postnatally) were found to have elongated nipples and enlarged pituitaries. The mammary gland whole mounts from all rats in groups 4 and 6 displayed extensive lobuloalveolar proliferation comparable to that seen in DES pellet controls (group 2). Mammary glands of approximately 75% of rats in groups 3 and 5 were categorized as showing the lowest grade of differentiation while this undifferentiated condition was seen in only 36% of group I controls. No palpable mammary tumors were found in rats exposed to vehicle in utero (group 1). But in group 5, a total of 6 tumors in 5 animals derived from 4 different litters were obtained, a difference shown to be statistically significant. Group 3 had 1 rat with 8 tumors. Among rats bearing the DES pellet, tumor latency was shortened significantly in both groups exposed to DES in utero. By 22 weeks after pellet implantation, 100% of the DES-exposed litters (groups 4 and 6) contained at least 1 tumor-bearing rat compared to about 50% of the tumor-bearing litters in group 2. Tumor multiplicity at sacrifice was increased significantly in the group exposed prenatally to the higher dose of DES. Histologically, the overwhelming majority of palpable mammary tumors from all tumor-bearing treatment groups were classified as adenocarcinomas. Prenatal exposure to DES did not alter the ratio of malignant to benign lesions observed, nor did it affect the degree of differentiation noted in the adenocarcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1987

Effects of intermittent diethylstilbestrol diphosphate administration on the R3327 rat prostatic carcinoma.

Clinical trials have utilized intermittent diethylstilbestrol diphosphate (DES) therapy in advanced symptomatic prostatic carcinoma to diminish the morbidity of standard endocrine therapy. To determine the effect of intermittent DES administration on the Dunning R3327 rat prostatic adenocarcinoma 60 days following tumor implant, 6 groups were randomly assigned: control (N = 8), castrate (N = 10), high dose DES (N = 8, 1.6 micrograms/ml DES continuously in drinking water), low dose DES (N = 10, 0.4 microgram/ml continuously in drinking water), intermittent high dose DES (N = 10, 1.6 micrograms/ml DES in drinking water for 1 week, then off for 3 weeks), and intermittent low dose DES (N = 10, 0.4 microgram/ml DES for 1 week, then off for 3 weeks). Results indicate that low or high dose DES, and intermittent low or intermittent high dose DES during the week of administration were able to reduce serum testosterone to castrate levels (0.1 ng/ml). After withdrawal of intermittent DES, serum testosterone returned toward control levels (1.0 ng/ml). Initial mean tumor burden between control and treatment groups was not significantly different. All DES exposed rats had a tumor volume at death (range, 15.6-18.3 cm3) smaller than control (mean, 25.4 cm3) or castrate (mean, 40.8 cm3) rats. Despite this significant survival advantage from the time of randomization was achieved only in castrate (median survival, 331 days) or high dose DES (median survival, 359 days) groups compared to control (median survival, 225 days). Similarly, significant prolongation in tumor doubling time was achieved only by rats receiving castration or high dose DES. Intermittent DES administration controls tumor volume but does not provide a survival advantage. In this respect, intermittent DES is inferior to castration.

Animals↗
PubMed1986

Intractable primary infertility in women exposed to diethylstilbestrol in utero.

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls. Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls. When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls. Primary infertility of one to two years' duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

Adult↗
PubMed1986

Hormonal imprinting by steroids: a single neonatal treatment with diethylstilbestrol or allylestrenol gives rise to a lasting decrease in the number of rat uterine receptors.

Binding of hormone by the uterine receptors of 6 week old rats treated with diethylstilbestrol (DES) or allylestrenol (AE) in neonatal age differed considerably from the controls. Both pretreatments accounted for a decrease in the number of Type II binding sites for estradiol without altering receptor affinity. It follows that steroids, too, are able to induce a hormonal imprinting during the critical stage of receptor maturation.

Allylestrenol↗
PubMed1986

Paraovarian cysts associated with prenatal diethylstilbestrol exposure. Comparison of the human with a mouse model.

The association of prenatal exposure to diethylstilbestrol (DES) and abnormalities in structures of müllerian (paramesonephric) origin has been well documented. In a murine model, exposure to DES in utero results in persistent mesonephric remnants in adult female mice. Six women exposed prenatally to DES had paraovarian cysts excised during routine gynecologic surgery; and in 4, histologic abnormalities were observed, including thickened fibromuscular walls with tall columnar epithelium in a papillary or pseudoglandular configuration. Four of 25 nonexposed and 8 of 9 DES-exposed infertile women undergoing surgery for infertility had paraovarian cysts, and the difference was statistically significant (P less than 0.02). These findings raise the possibility that structures derived from the mesonephric ducts or tubules may also be affected in women exposed in utero to DES.

Animals↗
PubMed1986

[Plasma concentrations of fosfestrol as well as diethylstilbestrol on their conjugates following intravenous administration on prostatic carcinoma patients].

After the identification of E-diethylstilbestrol (DES)-glucuronide-sulphate-bis-conjugate in the plasma of patients suffering from metastatic prostatic cancer for the first time we have registered the plasma concentration-time curves of fosfestrol (Honvan) and its monophosphate as well as E-DES and its 3 conjugates over 8 h with a further 10 patients. Maximum concentrations fluctuate between 1 and 32 micrograms/ml plasma. Therefore the greatest amount of E-DES formed by hydrolysis and its conjugates are hidden in deeper compartments, probably in the lung. The oxidative metabolism of E-DES compared with its conjugation reactions is less important. Only E-DES monoglucuronide and small amounts of E-DES-glucuronide-sulphate-bis-conjugate are detectable in urine. Renal excretion of those metabolites which are in the enterohepatic circle in form of E-DES-glucuronide and E-DES-glucuronide-sulphate-bis-conjugate could be observed even over a period of 72 h.

Aged↗
PubMed1986

Influence of single neonatal treatment with allylestrenol or diethylstilbestrol on microsomal enzyme activity of rat liver in adulthood.

A single neonatal treatment of rats with a steroid (allylestrenol or diethylstilbestrol) did not alter the later activity of the hepatic microsomal (cytochrome P-450) enzyme system, but inhibited the inducer action of another steroid (testosterone) administered at the age of six weeks. This suggests that a hormonal imprinting-like mechanism also operates in the case of enzymes.

Allylestrenol↗