Cancer Risk in Women Exposed to Diethylstilbestrol In Utero

Hatch, Elizabeth E.; Palmer, Julie R.; Titus-Ernstoff, Linda; Noller, Kenneth L.; Kaufman, Raymond H.; Mittendorf, Robert; Robboy, Stanley J.; Hyer, Marianne; Cowan, Charise M.; Adam, Ervín; Colton, Theodore; Hartge, Patricia; Hoover, Robert N.

doi:10.1001/jama.280.7.630

Cited by 175 publications

(81 citation statements)

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“…63,64 In a recent cohort study, the incidence of endometrial carcinomas in DESexposed persons was lower than that of unexposed persons. 65 These findings in human might be consistent with this study using the mice model.…”

Section: Discussionsupporting

confidence: 90%

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

Begum

Tashiro

Katabuchi

et al. 2006

Laboratory Investigation

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Human endometrial carcinomas, as well as complex atypical hyperplasias (CAH), are estrogen related and frequently have mutations in the PTEN gene. However, the mutual contribution of estrogen and PTEN mutations to endometrial carcinogenesis in vivo is unknown. To address this issue, we investigated whether neonatal estrogenic treatments augment the incidence of CAH and carcinomas in murine PTEN (mPTEN) heterozygous ( þ /À) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 lg/g/day) in phytoestrogens, estriol (E 3 ) (4 lg/g/day), and vehicle (ethanol and corn oil) were administered subcutaneously daily to neonatal pups from the 1st to 5th day after birth. At 52 weeks of age, the morphological changes in the endometrium, and uterine expression of Hoxa 10 and Hoxa 11, were evaluated. These Hoxa genes are abdominal B-type homeobox genes, which normally regulate differentiation of the Mü llerian duct. The incidence of CAH and adenocarcinomas of the endometrium was significantly decreased by the neonatal estrogenic treatments in the mPTEN þ /À mice. Coincidentally, all treatments significantly decreased the stromal cell density, and CAH and adenocarcinomas rarely developed in the epithelium adjacent to the affected endometrial stroma. Moreover, the uterine expression of Hoxa 10 in mice with neonatal genistein and E 3 treatments, and that of Hoxa 11 in mice with all treatments, was significantly lower when compared with vehicle alone. Taken together, neonatal estrogenic exposure induced stromal atrophy and/or hyalinization accompanied by repressed expression of Hoxa 10 and Hoxa 11, and exerted an inhibitory effect on PTEN-related tumorigenesis. These findings provide new insight into the interaction between endometrial epithelium and stroma in endometrial carcinogenesis in vivo.

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Section: Discussionsupporting

confidence: 90%

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

Begum

Tashiro

Katabuchi

et al. 2006

Laboratory Investigation

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“…With respect to specific cancers, there was an excess of only CCA of the vagina and cervix. Previously, we published incidence rates for CCA among the DES-exposed women 4 and the additional follow-up presented here continues to inform on the shape of the incidence curve. Our data on CCA are based on small numbers but confirm that the major excess RR is in adolescence and early adulthood as described before.…”

Section: Discussionmentioning

confidence: 85%

“…The age-adjusted RR for total cancer mortality was 0.98 (95 % CI 0.46-2.1). The standardized mortality ratios for allcause and cancer-specific mortality were below 1.0 for both the Incidence rate ratios (RR) are adjusted for age in 5-year categories.-2 Standardized incidence ratio (SIR) using age-and calendar-year-specific SEER rates for white females to obtain expected values; Confidence interval (CI).-3 All-cancer includes ICD9 codes 140-208 excluding melanoma (172), nonmelanoma skin (173) and cervix (180); CCA includes 3 vaginal and 1 cervix; other sites include non-CCA vaginal (1 exposed), kidney (2 exposed, 1 unexposed), mouth (1 exposed, 1 unexposed), thymus (1 exposed), connective tissue (1 exposed), head/neck (1 exposed), pancreas (1 exposed), esophageal (1 exposed), stomach (1 unexposed) and unspecified (1 exposed).- 4 Person-time for the Poisson regression analyses stops at the date of bilateral oophorectomy for ovarian cancer, and at the date of hysterectomy for endometrial cancer. exposed and unexposed participants when compared with population rates.…”

Section: Resultsmentioning

confidence: 99%

“…Baseline findings limited to analysis of the previously established cohorts showed DES was associated with an excess CCA risk and possibly with elevated breast cancer risk in older women, but did not indicate greater risk of endometrial or ovarian cancer. 4 More recent follow-up of the cohort for breast cancer incidence has shown a small but progressively increasing risk for DES exposure with age after 40. 5,6 To date, the follow-up experience of the combined cohort with regard to overall and reproductive tract cancer risk has not been characterized.…”

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confidence: 99%

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Cancer risk in women prenatally exposed to diethylstilbestrol

Troisi

Hatch

Titus-Ernstoff

et al. 2007

Intl Journal of Cancer

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158

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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 calendaryear specific standardized incidence rate ratios (SIR), and ageadjusted 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. ' 2007 Wiley-Liss, Inc.Key words: diethylstilbestrol; estrogen; cancer Diethylstilbestrol (DES), a potent synthetic estrogen, was first synthesized in 1938 and shortly thereafter promoted to prevent spontaneous abortion and premature delivery. 1 Over the next three decades, DES was administered to several million pregnant women in the United States and Europe. In 1971, a strong association was reported between DES and clear cell adenocarcinoma (CCA) of the vagina and cervix in young women. 2 Animal studies suggest the teratogenic and carcinogenic effects of prenatally administered DES may be due to changes in the expression of genes involved in the development of the reproductive tract 3 and raise concerns of elevated risk of other female reproductive tract cancers besides CCA.In the early 1990s, the National Cancer Institute (NCI) assembled new and previously established cohorts of DESexposed and unexposed individuals for combined follow-up. Baseline findings limited to analysis of the previously established cohorts showed DES was associated with an excess CCA risk and possibly with elevated breast cancer risk in older women, but did not indicate greater risk of endometrial or ovarian cancer. 4 More recent follow-up of the cohort for breast cancer incidence has shown a small but progressively increasing risk for DES exposure with age after 40. 5,6 To date, the follow-up experience of the combined cohort with regard to ove...

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“…As part of the ongoing follow-up of DES-exposed cohorts, substantial numbers of exposed males and females have been studied. Depending on the timing ofexposure and the total maternal DES dose administered, unequivocal (and more readily observed) effects seen in males and females include reproductive tract malformations, impaired reproduction, and vaginal carcinoma (29)(30)(31)(32)(33). More equivocal effects include decreased sperm count (34)(35)(36), immune dysfunction (37), alterations in sexual behavior (38), disturbed menstrual cycles (39), and testicular cancer (40).…”

mentioning

confidence: 99%

New approaches for estimating risk from exposure to diethylstilbestrol.

Cunha

Forsberg

Golden

et al. 1999

Environ Health Perspect

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A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans. (4,5) and were thought to cross the placenta in humans (6,7), direct evidence of teratogenicity of estrogens in humans was unknown until after the association between DES and vaginal adenocarcinoma was reported. In any case, despite the tragedy of the DES episode, the human DES clinical data offer an unprecedented opportunity to learn about the consequences of in utero exposure to a potent estrogen and thus to infer potential risks following exposure to less potent environmental estrogens.If properly interpreted, lessons from the DES episode may prove invaluable for judging potential effects of compounds that have been or will be identified as potential endocrine disruptors. It will be important, however, to keep in mind the considerable differences in potency between such compounds when inferences are drawn concerning potential effects. For example, the carcinogenicity of DES was identified in a human study including only 8 cases and 32 controls (8). Normal sample size calculations would rule such a study as inadequate. However, because the cancer induced by DES (clear cell vaginal adenocarcinoma) was so rare in young women, the association between prenatal DES exposure and development of clear cell adenocarcinoma of the vagina was easily identified. Clearly, most chemicals with significantly less potent endocrine (e.g., estrogenic) effects will convey much-reduced risks, particularly at low doses. Thus, study designs for other endocrine disruptors will have to be more precise and more powerful, especially if the background incidence of a particular lesion is substantial. Given the history of the DES episode, we have considered this issue: If DES were introduced into the market for human use today and were likely to result in ...

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Cancer Risk in Women Exposed to Diethylstilbestrol In Utero

Cited by 175 publications

References 31 publications

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

Cancer risk in women prenatally exposed to diethylstilbestrol

New approaches for estimating risk from exposure to diethylstilbestrol.

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