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PubMedDate not supplied

Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol.

Thirty women with a history of prenatal exposure to diethylstilbestrol (DES) underwent a detailed sexual history and were compared to a demographically similar sample of 30 women with a history of an abnormal Pap smear. The DES women were found to have less well-established sex-partner relationships and less experience with child-bearing, to be lower in sexual desire and enjoyment, sexual excitability, and orgasmic coital functioning, but to be comparable (and low) with regard to such sexual dysfunctions as vaginismus and dyspareunia. Both potential psychosocial and neuroendocrine explanations are discussed.

Adult↗

PubMedDate not supplied

Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol (DES).

Previous research has suggested increased psychopathology in prenatally diethylstilbestrol (DES)-exposed persons. The current study compares the psychiatric histories and social functioning of 27 men with a history of high-dose prenatal DES exposure and their unexposed brothers. We expected DES subjects to show greater lifetime psychopathology and poorer social functioning than controls. Both groups showed high rates of lifetime depression, lifetime alcoholism, and current psychiatric symptoms in excess of community norms. The only diagnosis on which DES subjects exceeded their unexposed brothers was Major Depressive Disorder (MDD). DES-exposed men had almost twice the prevalence of at least one episode of MDD and had significantly more recurrent episodes. The relatively small number of subjects with concomitant lack of statistical power may have contributed to the difficulty obtaining significant effects.

Adult↗

PubMed1986

Diethylstilbestrol in pregnancy: an update.

Several decades ago, diethylstilbestrol (DES) was considered efficacious in improving pregnancy outcome. Later data did not support this, and the exposed mothers and offspring have suffered from a variety of problems attributed to the drug. Knowledge of these problems is essential in dealing with these patients.

Adenocarcinoma↗

PubMed1986

Terminal deoxynucleotidyl transferase negative acute lymphoblastic leukemia in two offspring of mothers exposed to diethylstilbestrol (DES) in utero.

We report two children with leukemia who were born to diethylstilbestrol (DES)-exposed mothers. The children were 2 and 6 years old at diagnosis and the lymphoblasts expressed the unusual terminal deoxynucleotidyl transferase negative phenotype. Both children completed induction and maintenance therapy and are alive 6 and 4 years from diagnosis. The role of DES as a transplacental carcinogen is reviewed, and a hypothesis for the target cell interaction is proposed.

DNA Nucleotidylexotransferase↗

PubMed2003

Ovarian carcinoma in an adolescent with transgenerational exposure to diethylstilbestrol.

Small cell carcinoma of the ovary is rare in adolescence. The etiology of such tumors is unknown. Several reports suggest that transgenerational exposure to diethylstilbestrol (DES) may have deleterious effects on the genitourinary tract. The authors describe a 15-year-old girl with small cell carcinoma of the ovary whose maternal grandmother had been taking DES while she was pregnant with the patient's mother. This case, while anecdotal, suggests that a transgenerational history of DES exposure should be noted, and that granddaughters with persistent abdominal pain even during childhood may need evaluation for genital tract abnormalities.

Abdominal Pain↗

PubMed2005

Six cases of women with diethylstilbestrol in utero demonstrating long-term manifestations and current evaluation guidelines.

Diethylstilbestrol (DES), a nonsteroidal estrogen, was widely used in the United States from 1940 through 1971 to prevent pregnancy loss. In the late 1960s, an association was made with an increased incidence of clear cell adenocarcinoma in young women exposed in utero to DES. Additional study of these women over the next 35 years has shown an increased risk of other health problems including intraepithelial neoplasia, ectopic pregnancy, first trimester spontaneous abortion and second trimester pregnancy loss. The National Institutes of Health continues to fund studies to follow cohorts of DES-exposed mothers, daughters, sons and third generation children. The Centers for Disease Control have conducted a large DES Education Project and have established guidelines for management. The following six cases studies illustrate common problems seen in DES exposed daughters and management of problems encountered.

Adenocarcinoma, Clear Cell↗

PubMed2005

Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure.

OBJECTIVE: To investigate the association between prenatal diethylstilbestrol (DES) exposure and risk of benign gynecologic tumors. METHODS: We conducted a collaborative follow-up study of women with and without documented intrauterine exposure to DES. We compared the incidence of self-reported ovarian cysts, paraovarian cysts, and uterine leiomyomata confirmed by medical record in DES-exposed and unexposed women. RESULTS: A total of 85 cases of uterine leiomyomata and 168 cases of ovarian or paraovarian cysts were confirmed histologically. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine leiomyomata. Prenatal DES exposure was positively associated with paraovarian cysts. CONCLUSION: The present results do not support the hypothesis that prenatal DES exposure increases risk of uterine leiomyomata or ovarian cysts. Prenatal DES exposure was associated with an increased risk of paraovarian cysts, but detection bias cannot be ruled out as an explanation of this finding.

Adolescent↗

PubMed2003

Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol.

BACKGROUND: Between 1939 and the 1960s, the synthetic estrogen diethylstilbestrol (DES) was given to millions of pregnant women to prevent pregnancy complications and losses. The adverse effects of prenatal exposure on the genitourinary tract in men and the reproductive tract in women are well established, but the possible effects on psychosexual characteristics remain largely unknown. METHODS: We evaluated DES exposure in relation to psychosexual outcomes in a cohort of 2,684 men and 5,686 women with documented exposure status. RESULTS: In men, DES was unrelated to the likelihood of ever having been married, age at first intercourse, number of sexual partners, and having had a same-sex sexual partner in adulthood. DES-exposed women, compared with the unexposed, were slightly more likely to have ever married (odds ratio [OR] = 1.1; confidence interval [CI] = 1.0-1.4) and less likely to report having had a same-sex sexual partner (OR = 0.7; CI = 0.5-1.0). The DES-exposed women were less likely to have had first sexual intercourse before age 17 (OR = 0.7; CI = 0.6-0.9) or to have had more than one sexual partner (OR = 0.8; CI = 0.7-0.9). There was an excess of left-handedness in DES-exposed men (OR = 1.4; CI = 1.1-1.7) but not in DES-exposed women. DES exposure was unrelated to self-reported history of mental illness in women. CONCLUSIONS: Overall, our findings provide little support for the hypothesis that prenatal exposure to DES influences the psychosexual characteristics of adult men and women.

Adult↗

PubMed2005

Hypospadias in sons of women exposed to diethylstilbestrol in utero.

BACKGROUND: Diethylstilbestrol (DES) is a synthetic estrogen that was widely prescribed to pregnant women before 1971. DES increases the risk of breast cancer in women who took the drug and the risk of reproductive tract abnormalities in their offspring. Dutch investigators have reported a 20-fold increase in risk of hypospadias among sons of women who were exposed to DES in utero. We assessed this relation in data from an ongoing study of DES-exposed persons. METHODS: Several U.S. cohorts of women with documented exposure in utero to DES have been followed by mailed questionnaires since the 1970s. Comparison subjects are unexposed women of the same ages. In 1997, participants were asked about congenital abnormalities in their children. We calculated prevalence odds ratios for the risk of hypospadias in sons of exposed mothers relative to sons of unexposed mothers using generalized estimating equations to adjust for multiple sons per mother and controlling for maternal age at the son's birth. RESULTS: We obtained data from 3916 exposed and 1746 unexposed women. These women reported a total of 13 liveborn sons with hypospadias (10 exposed, 3 unexposed). The prevalence odds ratio for risk of hypospadias among the exposed was 1.7 (95% confidence interval = 0.4-6.8). CONCLUSIONS: Our findings do not support a greatly increased risk of hypospadias among the sons of women exposed to DES in utero, as has been previously reported.

Diethylstilbestrol↗

PubMed2003

Enhancement of diethylstilbestrol induced cytotoxicity by bcl-2 antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer.

PURPOSE: Bcl-2 has been shown to prolong cancer cell survival by blocking apoptosis and have the function of scavenging reactive oxygen species. We assessed the efficacy of a novel strategy that relies on antisense bcl-2 oligodeoxynucleotides as well as a glutathione depletor combined with diethylstilbestrol (DES) for hormone independent prostate cancer. MATERIALS AND METHODS: The cytotoxic effects of antisense bcl-2 oligodeoxynucleotides and DES on PC-3 cells were determined using spectrophotometry measurement. The expression of Bcl-2 protein was detected by Western blot analysis. Intracellular reactive oxygen species generation was estimated from the amount of intracellular dichlorofluorescein. Apoptosis was determined by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling assay. RESULTS: Antisense bcl-2 oligodeoxynucleotides decreased Bcl-2 protein levels and significantly inhibited PC-3 cell growth in a dose dependent manner. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity. A significant increase in apoptotic cells was induced by the combination of antisense bcl-2 oligodeoxynucleotides and DES compared with the oligodeoxynucleotides alone. The glutathione depletor buthionine sulfoximine significantly decreased the intracellular concentration of glutathione and augmented DES induced cytotoxicity and reactive oxygen species generation in PC-3 cells. Neither the generation of reactive oxygen species nor the intracellular concentration of glutathione was influenced by antisense bcl-2 oligodeoxynucleotide treatment. CONCLUSIONS: Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells through the apoptotic pathway independent of augmented reactive oxygen species generation, whereas the glutathione depletor augmented cytotoxicity and reactive oxygen species generation.

Apoptosis↗

PubMed2003

The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer.

PURPOSE: During the last 2 decades there has been an increase in the number of men with prostate cancer placed on luteinizing hormone releasing hormone (LH-RH) agonist therapy. In addition, the duration of individual therapy has extended from what was once only a few months to, in many cases, several years. As a result there has been an increase in the incidence of side effects, including osteoporosis, decreased cognitive abilities, vascular stiffness and fatigue. We explored the use of estrogen in the form of diethylstilbestrol (DES) as an alternative treatment for men with prostate cancer, and introduce the concept of androgen deprivation without estrogen deprivation. In doing so we hope to elucidate some of the nonhormonal nonsteroidal effects of DES. Furthermore, we hope to define the mechanisms by which DES can be useful when LH-RH agonist therapy or orchiectomy has failed. MATERIALS AND METHODS: We comprehensively reviewed the literature from 1935 to the present regarding estrogen and antiandrogen therapy. Our search focused on issues pertaining to side effects, efficacy and nonsteroidal effects of antiandrogens and estrogens. RESULTS: It is readily apparent from the literature that androgen deprivation with DES can achieve effective prostate cancer control with demonstrable benefits compared to conventional LH-RH agonist therapy. In particular, rates of bone resorption and osteoporosis are less with the use of estrogen therapies. Estrogen has a clear beneficial effect on cognitive function. The estrogen metabolite 2-methoxyestradiol has significant antiangiogenic and pro-apoptotic effects. These effects give estrogens an added anticancer effect not otherwise seen in conventional LH-RH agonist therapy. CONCLUSIONS: The efficacy of 1 mg DES extends well beyond its androgen suppressive effects. Androgen deprivation without estrogen deprivation is a concept that deserves further attention in the urological community.

Androgen Antagonists↗

PubMed2005

Pseudoinfiltrative tubal metaplasia of the endocervix: a potential form of in utero diethylstilbestrol exposure-related adenosis simulating minimal deviation adenocarcinoma.

We report three cases of unusual tubal-type endocervical glandular proliferations simulating minimal deviation adenocarcinoma in women with a history of in utero diethylstilbestrol (DES) exposure. The lesions were characterized by haphazard glandular proliferations extending from 3.4 to 6.1 mm into the endocervical stroma and to the margins of excision in all cases. Most of the glands were small to medium-sized and round; some exhibited a moderate degree of cystic dilatation, and occasional glands had curvilinear profiles. The glandular epithelium displayed extensive tubal-type differentiation in all cases. In two cases, the glands lacked cytologic atypia and mitotic activity, and in one case, there was mild to moderate nuclear atypia with occasional mitotic activity. Immunohistochemical studies showed diffuse expression of estrogen and progesterone receptors and essentially no expression of p16 in two cases tested; there was no expression of CD10 in one case that was tested. The Ki-67 proliferation index was zero in one case and 25% in another. Human papillomavirus DNA was not detected by in situ hybridization in one case that was tested. The proliferations lacked features of mucinous and tubo-endometrioid types of minimal deviation adenocarcinoma. The clinicopathologic findings suggest the lesions are benign, and the association with in utero DES exposure raises the possibility that these could be a form of DES-related adenosis.

Adenocarcinoma↗

PubMed2001

Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta.

The orphan nuclear receptor ERR beta is expressed in undifferentiated trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERR beta results in abnormal trophoblast proliferation and precocious differentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol (DES) promotes coactivator release from ERR beta and inhibits its transcriptional activity. Strikingly, treatment of trophoblast stem cells with DES led to their differentiation toward the polyploid giant cell lineage. In addition, DES-treated pregnant mice exhibited abnormal early placenta development associated with an overabundance of trophoblast giant cells and an absence of diploid trophoblast. These results define a novel pathway for DES action and provide evidence for steroidlike control of trophoblast development.

Animals↗

PubMed2000

Selective solvent inclusion as a tool for mapping molecular properties in crystal structures: a diethylstilbestrol example.

Useful information about hydrogen bonding, the preferred modes of hydrophobic interaction and conformational preferences of a specific molecule can be obtained from cocrystallization of the solute with a selected series of solvent molecules. This method is used in a study of nine different crystal structures of diethylstilbestrol (DES) solvates. It is shown that solvent inclusion results not only in stronger hydrogen bonds, but usually also in a larger number of favorable C-H.pi interactions between DES molecules. Furthermore, solvent molecules such as DMSO, DMF, acetonitrile and acetone demonstrate important hydrogen-bond donating properties in addition to their more familiar role as hydrogen-bond acceptors. Molecular conformations in the crystal structures compare favorably with results from molecular mechanics calculations.

Acetone↗

PubMed1988

Inhibitory effect of tamoxifen on diethylstilbestrol-promoted hepatic tumorigenesis in male rats and its possible mechanism of action.

Male Sprague-Dawley rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg body weight). Two weeks later the rats were divided into 4 groups; DEN-C group rats were given no further treatment; DEN-DES group rats were fed diethylstilbestrol (DES, 0.5 mg/day); DEN-TMX group rats were given tamoxifen (TMX, 1.0 mg/day) orally; DEN-DES TMX group rats were fed both DES and TMX for 8 months. Rats of the DEN-DES group developed grossly visible hepatic tumors. On the other hand, tumor development was significantly inhibited in rats of the DEN-DES TMX group. Total area of gamma-glutamyl transpeptidase-positive lesions and the mean area per lesion were significantly larger in rats of the DEN-DES group than those of the DEN-C, DEN-TMX or DEN-DES-TMX group. Estrogen receptor (ER) content of liver cytosol assayed by enzyme immunoassay (EIA) was significantly greater in rats of the DEN-DES group than in those of the DEN-C group and smaller in rats of the DEN-TMX and DEN-DES TMX group than in the DEN-C group. On the contrary, ER content of liver nuclei was significantly greater in rats of the DEN-TMX and DEN-DES TMX group than in those of the DEN-C or DEN-DES group. These results suggest that the promotive action of DES and the inhibitory action of TMX on DES-promoted hepatic tumorigenesis are, at least in part, mediated by ER in the rat.

Animals↗

PubMed1993

Altered morphogenesis of the immature hamster uterus following neonatal exposure to diethylstilbestrol.

In previous studies, we found that a single neonatal exposure to diethylstilbestrol (DES) resulted in severe hyperplasia and a high incidence of endometrial adenocarcinoma in the uterus of adult hamsters. These observations prompted us to investigate the consequences of DES exposure on earlier stages of uterine morphogenesis. After neonates were treated within 6 h of birth (day 1) with 100 micrograms of DES or oil vehicle, uterine tissue morphometry plus cell labelling indices following in vivo pulse labeling with [3H]thymidine were determined on days 3-21 of life. The sequential findings were: (1) a precocious (day 3) burst of cellular proliferation throughout the uterus, (2) an early period (days 3-9) of hypertrophy and increased cell density in the luminal epithelium, (3) an extreme acceleration of uterine growth resulting in a persistent increase in total uterine mass (> threefold enhancement on days 5-21), (4) precocious development of endometrial glands (day 9) that were sites of intense but transient proliferative activity, (5) a middle period (days 9-15) when the percentage of stromal cells engaged in proliferative activity was reduced, (6) a second wave (days 15-21) of enhanced proliferative activity in the luminal epithelium, and (7) later development (day 21) of reduced cell density in the uterine stroma, apparently due to increased intercellular collagen accumulation. These results support our working hypothesis that the acute uterotropic response to neonatal DES treatment initiates a change in the developing hamster uterus, and later estrogenic stimulation promotes neoplastic progression in the DES-altered adult organ, perhaps due to disruption of stromal-epithelial interactions.

Age Factors↗

PubMed2004

Mouse bioassay to assess oestrogenic and anti-oestrogenic compounds: hydroxytamoxifen, diethylstilbestrol and genistein.

Young intact and adult gonadectomized C3H male and female mice were utilized as bioassay models to detect endocrine disruption chemicals. Animals treated with oestradiol (E) or progesterone (Prog) or E plus Prog were used to assess steroid hormone agonist and antagonist activities of 4-OH-tamoxifen (TAM), diethylstilbestrol (DES) and genistein (GEN) by bioassay. The stimulation or inhibition of mammary growth by TAM depended on sex, the state of animal (intact or gonadectomized), hormonal treatment (Prog, E, E plus Prog) and dose of TAM. TAM stimulated mammary growth in untreated ovariectomized (OV-X) females and in Prog-treated intact males and OV-X females. In intact males, mammary growth was increased by TAM at dose 0.1-1 microg day(-1) and decreased at dose 10 microg day(-1). Mammary growth was inhibited by TAM in Prog-treated intact females and in E or E plus Prog-treated intact and gonadectomized males and females. Uterine weights were increased by TAM in both untreated and treated (E, Prog, E plus Prog) intact and OV-X females; however, seminal vesicle weights were decreased by TAM in both untreated and treated (E, Prog, E plus Prog) intact males. DES alone affected mammary growth (an inverted-U-shaped dose-response curve) both in male and female mice. DES increased uterine weights; however, seminal vesicle weights were decreased. GEN increased mammary and uterine growth in OV-X females, GEN plus Prog stimulated mammary growth in intact males. The results obtained in these studies show clearly that only a bioassay consisting of several endpoints reflective to the mechanism of oestrogen and anti-oestrogen action has the ability to evaluate activities of a molecule.

Animals↗

PubMedDate not supplied

Detection of chromosomal aberrations by fluorescence in situ hybridization in cervicovaginal biopsies from women exposed to diethylstilbestrol in utero.

Epidemiologic studies have associated estrogens with human neoplasms such as those in the endometrium, cervix, vagina, breast, and liver. Perinatal exposure to natural (17beta-estradiol [17beta-E(2)]) and synthetic (diethylstilbestrol [DES]) estrogens induces neoplastic changes in humans and rodents. Previous studies demonstrated that neonatal 17beta-E(2) treatment of mice results in increased nuclear DNA content of cervicovaginal epithelium that precedes histologically evident neoplasia. In order to determine whether this effect was associated with chromosomal changes in humans, the frequencies of trisomy of chromosomes 1, 7, 11, and 17 were evaluated by the fluorescence in situ hybridization (FISH) technique in cervicovaginal tissue from 19 DES-exposed and 19 control women. The trisomic frequencies were significantly elevated in 4 of the 19 (21%) DES-exposed patients. One patient presented with trisomy of chromosomes 1, 7, and 11, while trisomy of chromosome 7 was observed in one patient. There were two patients with trisomy of chromosome 1. Trisomy of chromosomes 1, 7, 11, and 17 was not observed in the cervicovaginal tissue taken from control patients. These data suggest that DES-induced chromosomal trisomy may be an early event in the development of cervicovaginal neoplasia in humans.

Adenocarcinoma, Clear Cell↗