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Background Animal studies suggest that prenatal exposure to diethylstilbestrol (DES) causes epigenetic alterations in primordial germ cells that affect the next generation, but human studies are sparse. Methods We assessed hormonally mediated outcomes in third generation women whose mothers were prenatally DES-exposed and unexposed. Results Compared to the unexposed, DES-exposed third generation women had an increased risk of irregular menses and amenorrhea; the respective prevalence ratios and 95% confidence intervals (CI) in follow-up data were 1.32 (95% CI: 1.10, 1.60) and 1.26 (95% CI: 1.06, 1.49); associations were more apparent in third generation women whose prenatally DES-exposed mothers were affected by vaginal epithelial changes. The follow-up data also indicated an association with preterm delivery (relative risk (RR): 1.54; 95% CI: 1.35, 1.75). Conclusion DES third generation women may have an increased risk of irregular menstrual cycles, amenorrhea, and preterm delivery, consistent with inter-generational effects of endocrine disrupting chemical exposure in humans.

Clear-Cell Adenocarcinoma and DES Exposure Among 695 women with clear-cell carcinoma of the vagina and cervix who were followed for a median of nearly 23 years, 5-year survival was 86% among women with documented diethylstilbestrol exposure and 81% among those without such exposure.

Objective Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA) at younger age. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. The complete epidemiologic curve of CCA has not been reported, yet. Methods We reviewed 720 cases of CCA from the CCA registry at the University of Chicago through 2014. Incidence rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. Results In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% were among those between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 42. The risk of DES-related CCA was highest in the 1951–1956 birth cohort and this birth cohort effect closely correlated with DES prescriptions over time in the U.S. (r=0.98, P =0.005). By age 50, the cumulative risk of CCA was 1 per 750 exposed women. CCA cases without evidence of DES exposure had similar ages, year of diagnosis, and birth cohort patterns as the documented DES-exposed cases, suggesting that some negative cases were exposed. Their inclusion raises the cumulative risk of CCA to 1 per 520. Conclusion With the largest data available, our results confirmed the association between prenatal DES exposure and clear cell adenocarcinoma. The study also refines the risks of DES-related CCA.

Aims To provide representative data from routine diabetes care concerning the physical activity levels of people with Type 2 diabetes, and to show the association of activity level with cardio-metabolic risk profile in a gender-specific analysis. Methods The anonymized data from 65 666 subjects with Type 2 diabetes, who have been receiving treatment in specialized diabetes institutions, were analysed using a large multi-centre database. The population was categorized as physically inactive (PA0), active 1–2 times per week (PA1), active >2 times per week (PA2), and then stratified by age (20–59 and 60–80 years). BMI, glycaemic control (measured by HbA1c levels), blood pressure, lipid profile and therapeutic regimen were adjusted for age, gender and diabetes duration. Results Most subjects were inactive (PA0: 90%; PA1: 6%, PA2: 4%). BMI, HbA1c and lipid profiles were better in older subjects and hypertension rates were lower in younger subjects. In both age groups, BMI, HbA1c (both P

In utero diethylstilbestrol (DES) exposure is a risk factor for rare development of vaginal and cervical cancer and may potentially be a risk factor for breast cancer. Mammography use in this population is relatively unknown; therefore, this study aims to determine if in utero DES exposure is associated with the frequency of mammography screening examinations while considering demographic and clinical factors.Using combined DES cohort questionnaire data, self-reported mammography screening over the past 5 years (2001-2006) was analyzed in women aged ≥45 years. Binary logistic regression assessed if DES exposure was associated with mammography use after adjustment for benign breast disease (BBD), previous cancer diagnosis, and whether insurance access influenced screening use.Overall, the frequency of mammography examinations was similar for both DES-exposed and unexposed women. DES-exposed (n=2986) and unexposed women (n=1397) over the age of 44 reported receiving ≥3 mammography examinations in the past 5 years (73.8% and 74.0%, respectively). After adjustment, DES exposure was not associated with ≥3 mammograms in the past 5 years compared to ≤2 examinations (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.86-1.17), p=0.99).In utero DES exposure was not associated with mammography use, nor was health insurance status or a BBD or cancer diagnosis. Because of the potential elevated risk for breast cancer in women exposed prenatally to DES, continued monitoring of standard mammography recommendations is recommended for this group, which is predominantly over the age of 45.

Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood.We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero.Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes.In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990-1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (40 years of age), and mammographies, regardless of BBD history.The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.

Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed to > 2 million pregnant women in the mid-1900s. In later years, it was discovered to be associated with the occurrence of vaginal clear cell adenocarcinoma (Herbst et al. 1971), anatomic abnormalities of the reproductive tract (Stillman 1982), and poor reproductive outcomes in daughters (Beral and Colwell 1981; Kaufman et al. 2000; Palmer et al. 2001). DES exposure in utero may also exert long-term effects on female endocrine function, possibly leading to permanent dysregulation of the hypothalamic–pituitary–ovarian axis and alterations in hormone biosynthesis in adult women (Assies 1991; Peress et al. 1982; Wu et al. 1980). Although the effect of DES on plasma sex hormones has not been well studied, elevated levels of serum testosterone (Wu et al. 1980), but not luteinizing hormone (LH) (Peress et al. 1982; Wu et al. 1980), progesterone (Wu et al. 1980), or estrogens (Peress et al. 1982; Wu et al. 1980), have been documented in DES daughters. Levels of follicle-stimulating hormone (FSH) were elevated in DES-exposed women in one study, but no differences were found in LH or the ratio of FSH to LH (Peress et al. 1982); another study found no difference in FSH levels (Wu et al. 1980). Animal data show that in vitro production of testosterone, total estrogen, and progesterone by ovarian tissue was significantly greater in female mice exposed prenatally to DES, at all ages studied (Haney et al. 1984). Secondary sex ratio (proportion of male births)—a prevalence measure that reflects both sex programming at the time of conception and survival until birth—may be influenced by exposure to endocrine disruptors such as DES. In humans, several studies have examined the relation between preconceptual exposure to endocrine-disrupting compounds and secondary sex ratio, but most associations were observed in men and were mixed in direction (James 2006). With respect to maternal exposure, a significant decrease in sex ratio was found in studies of polychlorinated biphenyls (PCBs) (Weisskopf et al. 2003) and mercury (Sakamoto et al. 2001), but the majority of studies have been null, including those that examined maternal exposure to dioxin (Mocarelli et al. 2000; Rogan et al. 1999; Ryan et al. 2002; Yoshimura et al. 2001), PCBs (del rio Gomez et al. 2002; Karmaus et al. 2002; Taylor et al. 2006; Taylor et al. 1989), lead (Jarrell et al. 2006), and dichlorodiphenyltrichloroethane (DDT) (Cocco et al. 2006; Karmaus et al. 2002). Moreover, dose and timing of exposure have been incompletely characterized in many studies, and little is known about the relation of these chemicals to the maternal endogenous hormonal milieu. For instance, PCBs have estrogenic, antiestrogenic, and androgenic properties (Bonefeld-Jorgensen et al. 2001), making the direction and magnitude of their effects difficult to predict. In a small study of preconception maternal PCB concentrations that stratified by hormonal activity of the PCB, Taylor et al. (2006) found that the odds of a male birth were elevated among women exposed to estrogenic but not antiestrogenic PCBs. Although not statistically significant, these results suggest that PCBs have different biologic effects depending on their underlying hormonal activity. A prevailing hypothesis is that endocrine disruptors such as DES may affect secondary sex ratio through changes in hormonal concentrations around the time of conception (James 1987). In women, high levels of gonadotropins (FSH and LH) and progesterone are hypothesized to change the ratio toward more girls, whereas high testosterone and estrogen levels change the ratio toward more boys (James 1987). Another hypothesis, the “over-ripeness ovopathy” theory (Jongbloet 2004), postulates that sex ratio is influenced by both oocyte maturation and the quality of cervical mucus, with nonoptimal hormonal modulation favoring male-biased progeny. Nonoptimal liquefaction of cervical mucus may facilitate differential migration of sperm, with increased fertilization by Y-bearing sperm because the head, length, perimeter, and area are significantly smaller and the neck and tail are shorter in Y-bearing sperm than in X-bearing sperm (Cui 1997). Because concurrence of both oocyte maturation and cervical mucus liquefaction is modulated by estrogens before the midcycle, any perturbations to the endogenous estrogenic milieu caused by endocrine disruptors may theoretically affect sex ratio (Jongbloet 2004). To our knowledge, there are no studies of secondary sex ratio in women exposed to DES, either prenatally or preconceptually, and most animal studies of this association are null. Specifically, studies in female mice (Honma et al. 2002; Suzuki et al. 2002), rats (Odum et al. 2002), and Chinese rare minnows (Zhong et al. 2005) have found no association between prenatal DES exposure and secondary sex ratio, whereas studies in rats exposed pre-conceptually to DES had an increased proportion of male offspring (Sharpe et al. 1995). We evaluated the association between in utero DES exposure in women and the secondary sex ratio of their offspring in a large collaborative study of participants with and without documented exposure to DES. Based on previous studies of sex steroid hormone levels in women exposed in utero to DES and the possible influence of these hormones on sex ratio (James 1987), we hypothesized that DES-exposed women would have a higher proportion of male offspring than unexposed women.

To assess whether preeclampsia risk is elevated in pregnancies of diethylstilbestrol (DES)-exposed daughters.This study used data from the National Cancer Institute DES Combined Cohorts Follow-up Study. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7,313 live births (4,759 DES exposed and 2,554 unexposed). Poisson regression analysis estimated relative risks and 95% confidence intervals (CI) for preeclampsia adjusted for age at the index pregnancy, parity, education, smoking, body mass index, year of diagnosis, and cohort.In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk. Adjustment for preeclampsia risk factors attenuated the relative risk slightly (1.42, 95% CI 1.04-1.94). The excess risk with DES was concentrated among women who developed preeclampsia in their first pregnancies (relative risk 1.81, 95% CI 1.17-2.79), who were exposed before 15 weeks of gestation (relative risk 1.57, 95% CI 1.11-2.23), and who were treated with magnesium sulfate (relative risk 2.10, 95% CI 0.82-5.42). Among DES-exposed women who had a prior hysterosalpingogram, preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%).These data suggest that in utero exposure to DES is associated with a slightly elevated risk of preeclampsia, and that one possible biological mechanism involves uterine abnormalities.

BACKGROUND: The initial period of diabetes type 1 is of great importance, since early metabolic adjustment has profound impact on long term control. The majority of pediatric centers in Germany participate in a national quality initiative, providing longitudinal data for central analysis. PATIENTS: 104543 anonymous data sets were obtained from 6123 pediatric patients under 18 years who were treated in 157 pediatric centers and monitored for 36 months at the same center starting from diagnosis. RESULTS: Partial remission (insulin

Women in the 1940s-1960s were prescribed diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women.National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models.DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization.Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group.

It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages ≥40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages ≥50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1509–14)

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

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.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.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).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.

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.

BACKGROUND: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer.

Objective: Women exposed to diethylstilbestrol (DES) in utero are at increased risk for the development of vaginal and cervical clear cell adenocarcinoma (CCA), and possibly of breast cancer, diabetes, and cardiovascular diseases as well. A peak in the age-incidence curve in DES- related CCA has been documented at ages 19 to 24. It is unknown if a second peak will occur in later life, the ages when CCA developed spontaneously in the pre-DES era. In addition, the long-term prognosis and health impact for adolescents and young adults who have DES-related CCA are unknown. Methods: 720 cases of CCA were reviewed from the CCA Registry at the University of Chicago through 2014. Rates and cumulative risks for CCA were calculated based on white women born in the U.S. from 1948 through 1971. Kaplan-Meier method was used to estimate survival probability among women with CCA. Cox models were used to identify independent prognostic factors. To gauge the relative impact of young-onset clear-cell adenocarcinoma on mortality, we compared their mortality hazards with mortality hazards of the U.S. female population, and calculated standardized mortality ratio (SMR). Results: In 420 CCA cases there was documented evidence of prenatal DES exposure. 80% patients had a CCA between ages 15 and 31 but some occurred as late as age 55. A small second peak occurred around age 40. The risk of U.S. born, white DES-related CCA was highest in the 1951-1956 birth cohort, and this birth cohort effect correlated with DES use in the U.S. By age 50, the cumulative risk of CCA was 1 per 750 exposed women. A total of 695 CCA patients were included in the survival analysis. After a median follow-up of 22.7 years (interquartile range: 10.8-35.1 years), 219 patients died. The 5-year, 10-year, and 20-year survival probabilities were 83%, 75%, and 69%, respectively. As expected, tumor stage was a strong prognostic factor for survival among DES-related CCA cases. Tubular-cystic histology was associated with better survival compared with papillary, solid, or a combination of these histological patterns. Adolescent patients ( Conclusion: Our study drew a relatively complete epidemic curve of DES-related CCA. There existed late-onset CCA among women with prenatal exposure of DES. DES-related CCA increased mortality not only during early life among exposed women, but also impacted life after age 50. These results suggest continued close health follow-up of this population. Citation Format: Dezheng Huo, Diane Anderson, Arthur L. Herbst. Incidence and mortality of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: 40 years of long-term follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 709. doi:10.1158/1538-7445.AM2017-709

Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy. In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility. A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5), and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1). Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively. The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07–1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

Objectives: Women exposed prenatally to diethylstibestrol (DES) have an excess risk of clear-cell adenocarcinoma of the vagina and cervix, but the effect on the incidence of squamous neoplasia is uncertain. The purpose of the current study was to evaluate the long-term risk of developing high-grade squamous neoplasia of the genital tract among women exposed prenatally to DES. Methods: A cohort comprising 3899 DES-exposed and 1374 unexposed daughters was followed for 13 years (1982–1995) for pathology-confirmed diagnoses of high-grade squamous intraepithelial neoplasia (HSIL) of the genital tract. Poisson regression analysis was used to compute relative risks (RR) and 95% confidence intervals (95% CI), adjusting for age, calendar year, and other covariates. Results: The RR (95% CI) among DES-exposed versus unexposed, based on 111 cases of high-grade disease, was 2.1 (1.2–3.8). Adjustment for screening history estimated by the number of years since the last Pap smear had little effect. Risk estimates were higher with earlier intrauterine exposure; the RR (95% CI) for exposure within 7 weeks of the last menstrual period was 2.8 (1.4–5.5). Only two cases of invasive squamous cervical cancer occurred in total, precluding separate analysis. Conclusions: The findings support an association between in-utero DES exposure and high-grade squamous neoplasia, although a role for more intensive screening among DES-exposed women in the production of this excess could not be completely ruled out.

Objective: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. Methods: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. Results: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). Conclusion: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

Objective: To assess the influence of postnatal factors on the development of clear cell adenocarcinoma in women exposed to diethylstilbesterol (DES), particularly factors related to exogenous or endogenous hormone exposures, and to reassess the relation of season of birth. Methods: For the analysis of postnatal factors, 244 cases were compared with 244 age-matched DES-exposed women. Information was obtained from telephone interviews, with questions asked in reference to an index age, the age at which clear cell adenocarcinoma was diagnosed. For the analysis of season of birth, 604 cases, living or deceased, were compared with 1749 DES-exposed women. Results: Neither oral contraceptive (OC) use nor pregnancy was associated with risk of clear cell adenocarcinoma: the odds ratios (OR) were 1.1 (95% confidence interval [CI] 0.7, 1.8) for OC use and 1.3 (95% CI 0.7, 2.3) for pregnancy. The OR for fall season of birth relative to all other seasons was 1.2 (95% CI 0.9, 1.4). Conclusion: Pregnancy and OCs do not increase risk of DES-associated clear cell adenocarcinoma. In addition, season of birth does not appear to be a material factor; the previous finding of an increased risk for fall season of birth is most likely not valid and probably a chance finding due to small sample size.

Although establishing sexual relationships is viewed as an important developmental milestone for adults, sexual functioning has been a neglected area of investigation for survivors of gynecological cancer. This article describes the long-term effects of clear-cell adenocarcinoma, with a specific focus on sexual functioning as a major quality-of-life concern. The authors hypothesized that respondents with multiple factors that interfered with their sexual functioning would report greater sexual dysfunction, poorer adjustment, and relationship difficulties. Two additional goals were to describe late psychological effects, such as depressive symptoms, and to explore the relationship between health status, coping behavior, social support variables, and depressive symptoms. The findings provide preliminary support for a complex relationship between medical complications, sexual dysfunction, emotional adjustment, and marital/partner relationships: 38% of the respondents reported physical and psychosexu...

Diethylstilbestrol (DES), a synthetic estrogen that was used in pregnancy, is a prototype endocrine-disrupting chemical. Although prenatal exposure to DES is known to increase risks of vaginal/cervical adenocarcinoma and adverse reproductive outcomes in women, and urogenital anomalies in men, data on nonreproductive medical conditions are lacking.We estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years.Comparing persons exposed prenatally to DES with those who were not exposed, the hazard ratios were 1.21 (95% confidence interval = 0.96-1.54) for diabetes, 1.27 (1.00-1.62) for all cardiovascular disease, 1.18 (0.88-1.59) for coronary artery disease, 1.28 (0.88-1.86) for myocardial infarction, 1.12 (1.02-1.22) for high cholesterol, 1.14 (1.02-1.28) for hypertension, 1.24 (0.99-1.54) for osteoporosis, and 1.30 (0.95-1.79) for fractures. The associations did not differ by dose and timing of DES exposure, nor, in the women, by the presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).These data raise the possibility that prenatal exposure to DES is associated with several common medical conditions in adulthood, although differential reporting by DES status and residual confounding cannot be ruled out. Further follow-up should assess these findings with validated outcomes and seek to understand the biological mechanisms.

Background Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia. Objective We explored whether neoplasia risk remains elevated among DES-exposed women as they age. Study Design In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort. Results The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1–6.5%) and in the unexposed group was 2.6% (95% CI, 1.5–3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33–2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33–2.93). The HR was 2.10 (95% CI, 1.41–3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age 15th week (HR, 1.14; 95% CI, 0.59–2.20). Conclusion CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits.

OBJECTIVES: As part of a larger health survey, we sought to determine whether prenatal exposure to diethylstilbestrol is associated with onset of early menopause or menopausal symptoms. STUDY DESIGN: Diagnosis of premature ovarian failure and symptoms of menopause were determined in a telephone interview with 542 women whose mothers participated in a randomized clinical trial of the use of diethylstilbestrol in pregnancy in the early 1950s. These women were aged 37 to 39 at the time of the interview. Medical records were obtained to confirm diagnosis of premature ovarian failure. RESULTS: The prevalence of menopausal symptoms (specifically hot flashes and night sweats) did not differ for exposed and unexposed women. One exposed woman and no unexposed women had a medically confirmed diagnosis of premature ovarian failure. CONCLUSIONS: Prenatal diethylstilbestrol exposure was not related to diagnosis or symptoms of menopause in this study. Further follow-up will be necessary to determine if a difference in age at menopause emerges as these women become older.

BACKGROUND Several genetic syndromes are associated with diabetes mellitus (DM). This study aimed to analyse data from the DPV database with regard to frequency, treatment strategies and long-term complications in paediatric DM patients with genetic syndromes, including Turner syndrome (TS), Prader-Willi syndrome (PWS), Friedreich ataxia (FA), Alstrom syndrome (AS), Klinefelter syndrome (KS), Bardet-Biedl syndrome (BBS), Berardinelli-Seip syndrome (BSS) and Down syndrome (DS). METHODS Longitudinal data for 43 521 patients with DM onset at age < 20 years were collected from 309 treatment centres in Germany and Austria using the DPV software. Data included anthropometric parameters, type of diabetes, mean age, age at diabetes onset, daily insulin dose, HbA 1c , micro- and macroalbuminuria, retinopathy and dyslipidaemia. Descriptive statistics and standard statistical tests were used for data analysis. RESULTS In total, 205 DM patients had one of the following syndromes: DS (141 patients), TS (24), PWS (23), FA (5), AS (5), KS (4), BBS (2) and BSS (1). Diabetes-specific antibodies were positive in the majority of patients with DS, TS and FA. CONCLUSION Despite the well-known association between DM and certain syndromic disorders, the number of affected patients in the German and Austrian paediatric diabetic population is very low. Nevertheless, physicians should be aware of syndromic forms of diabetes. Joint multicentre analyses are needed to draw relevant conclusions.

Most young women with clear-cell adenocarcinoma (CCA) of the vagina have a history of prenatal exposure to diethylstilbestrol (DES). Some, however, develop vaginal CCA without a prior history of DES exposure. We hypothesized that the natural history of DES-exposed vaginal CCA and DES-unexposed vaginal CCA may differ. Cases were identified from the Registry for Research on Hormonal Transplacental Carcinogenesis which maintains information on cases of CCA of the lower genital tract occurring in women born after 1940. Four hundred and thirty-one cases satisfied FIGO criteria for primary vaginal carcinoma of which 318 had prenatal, hospital, obstetrician, or pharmacy records available for review. Of these, 80% (255/318) had written documentation of prenatal exposure to DES (DES+) and 20% (63/318) had no evidence of DES exposure (DES-) in their medical records. DES exposure was undetermined in 113 cases due to lack of appropriate medical records. Among cases with documentation, DES exposure was not associated with mean age at diagnosis, (DES+, 20.3 years, DES-, 21.1 years), stage (stage I: DES+, 59%, DES-, 54%; stage II: DES+, 32%, DES-, 33%; stage III: DES+, 7%, DES-, 11%; stage IV: DES+, 2%, DES-, 2%, mean tumor diameter or surface area, grade, histology, cell type, or initial therapy. Among cases which underwent pelvic and paraaortic lymph node sampling (DES+, 63%; DES-, 56%; P = NS) the prevalence of pelvic node involvement was similar (DES+, 18.6%; DES-, 17.1%). However, only 1.2% (2/161) of DES+ cases had positive paraaortic lymph nodes compared to 8.6% (3/35) of DES- cases ( P = 0.041). Survival differed significantly between the two groups. Probability of survival at 5 and 10 years for DES+ cases was 84 and 78%, respectively, compared to 69 and 60%, respectively, for DES- cases (5 years, P = 0.007, and 10 years, P = 0.008). Presently, 21% (53/255) of DES+ cases are known to have died, compared to 37% (23/63) of DES- cases ( P = 0.008). Sites of disease recurrence also differed. DES- cases were more likely than DES+ cases to present with or to later develop distant tumor to the lungs (24% vs 9%; P = 0.002) or metastases to supraclavicular lymph nodes (8% vs 1.6%; P = 0.017). Among the 113 cases with an uncertain history of DES exposure, survival was intermediate between the well-documented cases (79% at 5 years and 65% at 10 years with 35/113 or 31% known dead), as was frequency of metastases to the lungs (13%) or supraclavicular lymph nodes (5.3%). Thus, the prognosis and metastatic behavior of CCA of the vagina appear to be influenced by DES exposure. DES negative cases have a worse prognosis and higher rate of distant metastasis than cases associated with exposure to DES. These observations do not appear to be due to differences in clinical prognostic factors such as tumor stage or diameter, but instead suggest differences in tumor behavior for as of yet undetermined reasons.

The objectives of this manuscript are to review the epidemiologic characteristics of ovarian cancer and to summarize the current status of tumor markers to detect disease.A review of the pertinent literature was done.In general, ovarian cancer is most frequent in industrialized countries, with dietary fat and possible use of talc as additive factors. Ovulation appears to increase the risk as does family history, increasing age, infertility, and possibly the use of ovulatory drugs. Pregnancy and the use of oral contraceptives, as well as possibly breast-feeding, lower the risk. Tubal ligation or hysterectomy with ovarian preservation also lowers the risk. The lifetime risk is about 1.4% in the United States, and the risk increases with age. If one first-degree relative has ovarian cancer, the lifetime risk appears to rise to 5%, but this pooled estimate may be affected by self-reporting bias in some studies. CA 125, the most widely used marker, is nonspecific, being elevated in about 80% of cases of ovarian epithelial cancer but also elevated in a number of benign conditions, which reduces its potential effectiveness as a screening tool.No single cause of ovarian cancer has been uncovered. Overall90% of ovarian cancers occur sporadically. Those with the hereditary ovarian cancer syndrome (multiple generations of breast and ovarian cancer) have a 50% risk and an autosomal dominant inheritance, but they constitute1% of cases. No ideal tumor marker for ovarian cancer screening is currently available. Further evaluation is needed to see whether the use of multiple tumor markers and/or vaginal ultrasonography might produce an acceptable cost-effective screening model. Current data do not support the utilization of prophylactic oophorectomy in women with one first-degree relative with ovarian cancer as a general strategy to prevent ovarian cancer. It is appropriate strategy for those with hereditary ovarian cancer syndrome.

A recently published study of the management of low-grade cytologic smears compared immediate colposcopy to human papillomavirus (HPV) triage and entry cytology smears (conservative management) as three triage techniques for managing atypical squamous cells of undetermined significance (ASCUS) smears (Atypical Squamous Cells of Undetermined Significance/Low-grade Squamous Intraepithelial Lesion Triage Study [ALTS]). The study reported a high sensitivity (96.3%) for HPV testing using hybrid capture 2 to detect cervical intraepithelial neoplasia (CIN) III. The authors concluded that HPV testing is a viable option for managing ASCUS smears. We have reviewed the published data from the ALTS trial and have found a large excess of colposcopies and biopsies in the HPV arm in comparison with the conservative management (cytology) arm. In addition, the ALTS trial quality control and pathology review results raise doubts about the diagnostic validity of the study to establish standards of clinical practice. Furthermore, until the 2-year follow-up analysis of the conservative management arm is completed to detect CIN III, a valid comparison between HPV triage and conservative management is not possible. We conclude that, based on published data, HPV testing for routine clinical management of low-grade cytologic abnormalities (ASCUS smears) is not warranted, and that HPV testing is currently an investigational tool.

Background Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results. Methods In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth. Results Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.13.4) for cryptorchidism, 2.5 (1.54.3) for epididymal cyst, and 2.4 (1.54.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.65.2) for cryptorchidism, 3.5 (2.06.0) for epididymal cyst, and 3.0 (1.75.4) for inflammation/infection of testes. Conclusion These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.

In the latter 1960s, 7 young women with vaginal cancers were treated in New England, primarily at the Massachusetts General Hospital. They were unique because of their young age (15-22 years) and the histologic characteristics of these vaginal tumors (clear cell adenocarcinomas). Dr Robert E. Scully and 11 published a clinicopathologic study of these tumors, and at that time their association with prenatal exposure to diethylstilbestrol (DES) was not known. We were aware, however, that the 7 cases exceeded the total number of these rare tumors in young women that could be identified in the world literature up to that time. These patients had been treated by the senior gynecologists at the Massachusetts General Hospital, Drs Howard Ulfelder (Chairman of Gynecology), Francis Ingersoll, and Thomas Green. As a junior facultymember, I also had been involved in their care. The mother of one of the patients related to Dr Ulfelder her concern that her prenatal care had included ingestion of DES, and she believed this may have been responsible for her daughter's tumor. A case-control epidemiologic study was planned to investigate the sudden occurrence of a cluster of these rare tumors in the Boston area. Dr David C. Poskanzer, a neurologist, was recruited because of his epidemiologic training, and Dr T.C. Colton, of the Harvard School of Public Health, was also consulted for his advice in the statistical design of the epidemiologic investigation. By the time the study had begun, there was an eighth patient who had also been treated elsewhere in Boston. We selected as controls for each patient 4 daughters from the birth records of New England hospitals in which the 8 patients had been born. A comprehensive epidemiologic questionnaire was designed to investigate the maternal, paternal, and patient health histories of the 8 subjects and 32 control subjects. During the course of the administrat ion of the questionnaire, another mother from the original 7 patients, whose daughter had died of the tumor, spontaneously reported that she "...had taken DES during pregnancy" and felt "certain" it was the cause of her daughter's cancer. The results of this study, which were published in the New England Journal of Medicine in 1971,2 showed that 7 of the 8 mothers of the daughters with cancer had taken DES for the treatment

Objective. To estimate whether women exposed in utero to diethylstilbestrol (DES) report receiving more cervical and general physical examinations compared to unexposed women. Materials and Methods. 1994 Diethylstilbestrol Adenosis cohort data are used to assess the degree of recommended compliance of cervical screenings found in 3,140 DES-exposed and 826 unexposed women. Participants were enrolled at 4 sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data, which included reported frequency over the preceding 5 years (1990-1994) of Papanicolaou smears and general physical examinations. Results. Diethylstilbestrol-exposed women exceeded the recommended frequency of Papanicolaou smear screenings [adjusted odds ratio (aOR) = 2.15, 95% CI (confidence interval) = 1.60-2.88] compared to the unexposed. This association held among those without a history of cervical intraepithelial neoplasia (aOR = 1.88, 95% CI = 1.35-2.62). Diethylstilbestrol-exposed women exceeded annual recommendations for physical examinations (aOR = 2.27, 95% CI = 1.16-4.43) among women without a history of chronic disease when compared to unexposed women. Conclusions. Most DES-exposed women are receiving cervical cancer screening at least at recommended intervals, but one third of the women are not receiving annual Papanicolaou smear examinations.

Background: Animal studies suggest that prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes epigenetic changes that may be transmitted to the next generation. Specifically, these studies show an elevated incidence of reproductive tumors in the female offspring of prenatally-exposed mice. Methods: We assessed cancer and benign pathology diagnoses occurring in the offspring of women whose prenatal exposure to DES (or lack of exposure) was verified by medical record. Our data arose from 2 sources: the mothers' reports of cancers occurring in 8216 sons and daughters, and pathology-confirmed cancers and benign diagnoses self-reported by a subset of 793 daughters. Results: Although statistical power is limited, our data are consistent with no overall increase of cancer in the sons or daughters of women exposed in utero to DES. Based on pathology-confirmed diagnoses reported by the daughters, we saw no association between DES and risk of benign breast disease or reproductive tract conditions. Based on 3 cases, the incidence of ovarian cancer was higher than expected in the daughters of women exposed prenatally to DES. Conclusions: Our data do not support an overall increase of cancer risk in the sons or daughters of women exposed prenatally to DES, but the number of ovarian cancer cases was greater than expected. While preliminary, this finding supports continued monitoring of these daughters.

The written obstetric records of maternal exposure to diethylstilbestrol (DES) were used as a criterion standard and compared with the DES exposure history recalled by mothers of women with vaginal, cervical, or indeterminable vaginal/exocervical clear cell adenocarcinoma. Among cervical cases, the sensitivity of maternal recall was 50% (N = 2), and its specificity was 100%. Among vaginal and vaginal/exocervical cases, this sensitivity was 72%; specificity was 60%; and the majority of these mothers who said they did not take DES were DES positive by written records. Thus investigators should avoid using maternal recall alone to measure DES exposure. Among subjects for whom written maternal obstetric records were available, 88% of vaginal cases and 46% of cervical cases were DES positive. the authors conclude that few cases of vaginal clear cell adenocarcinoma should occur in young women as the cohort of women exposed in utero to DES continues to age, whereas cases of cervical origin may continue to occur.

A therapeutic alternative to exenteration for large locally advanced vulvar carcinoma involving the rectum, anus, or vagina is the use of preoperative radiation followed by radical surgery. Between 1980 and 1988, 13 patients with Stage III and 3 with Stage IV vulvar carcinoma involving the rectum/anus, urethra, or vagina were treated with 4000 rad to the vulva and 4500 rad to the inguinal and pelvic nodes followed by a radical vulvectomy and inguinal lymphadenectomy 4 weeks later. The overall 5 year cumulative survival was 45%. Twelve tumors regressed after radiation with 62.5% of the patients having visceral preservation while in 4 patients there was no major response to radiation and urinary or fecal diversion was required. Of the 6 recurrences 4 were central and 2 distant. Three patients with central recurrences had tumor within 1 cm of the vulvectomy margin. Complications included wet desquamation, inguinal wound separation, lymphedema, and urethral strictures. There were no operative deaths. It is concluded that the use of preoperative radiation followed by radical vulvectomy may be an alternative to pelvic exenteration in selected patients with advanced vulvar lesions.

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 DES-exposed patients has varied from 7 to 34 years with the highest frequency from 14 to 22 years. The risk among the exposed is small and is on the order of 1 per 1,000. 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. Pregnancy does not appear to influence adversely the tumor characteristics or prognosis of patients who have developed these malignancies. Criteria for appropriate local therapy of small clear cell adenocarcinomas of the vagina are presented. Recurrent CCA has been observed as long as 20 years after primary therapy emphasizing the importance of prolonged follow-up.

Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age- and calendar-year specific standardized incidence rate ratios (SIR), and age-adjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure.

Age at natural menopause is related to several health outcomes, including cardiovascular disease and overall mortality. Age at menopause may be influenced by the number of follicles formed during gestation, suggesting that prenatal factors could influence menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s, is related to reproductive tract abnormalities, infertility, and vaginal cancer in prenatally exposed daughters but has not been studied in relation to age at menopause. The authors used survival analyses to estimate the risk of natural menopause in 4,210 DES-exposed versus 1,829 unexposed US women based on responses to questionnaires mailed in 1994, 1997, and 2001. DES-exposed women were 50% more likely to experience natural menopause at any given age (hazard ratio = 1.49, 95% confidence interval: 1.28, 1.74). Among women for whom dose information was complete, there were dose-response effects, with a greater than twofold risk for those exposed to >10,000 mg. The causal mechanism for earlier menopause may be related to a smaller follicle pool, more rapid follicle depletion, or changes in hormone synthesis and metabolism in DES-exposed daughters. Age at menopause has been related, albeit inconsistently, to several exposures, but, to the authors' knowledge, this is the first study to suggest that a prenatal exposure may influence reproductive lifespan.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.

Background In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES. Methods Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure. Results Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers' DES exposure and daughters' infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005). Conclusions The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.