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Outcome and follow-up of diethylstilbestrol (DES) exposed individuals

Elizabeth Hatch, PhD
Section Editors
Susan M Ramin, MD
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG


Diethylstilbestrol (DES) is a nonsteroidal estrogen first synthesized in 1938. It readily crosses the placenta. Exposure to DES during a critical period of organogenesis disorganizes the developing uterine muscle layers; causes maldevelopment of the uterotubal junction; and prevents stratification of the vaginal epithelium and resorption of vaginal glands, resulting in vaginal adenosis. In murine studies, the mechanism for DES-induced adenosis is blocked expression of Trp63 in Müllerian duct epithelium at epithelial estrogen receptor alpha [1]. DES has also been shown to alter normal programming of the gene families Hox and Wnt, which affect differentiation of the reproductive tract [2-6].

DES was initially used for postpartum lactation suppression and treatment of postmenopausal symptoms, but quickly became an accepted intervention for prevention of miscarriage, premature birth, and other pregnancy problems. It is estimated that five million pregnant women worldwide received DES to improve pregnancy outcome. Although clinical trials in the 1950s demonstrated that it was ineffective for prevention of adverse pregnancy outcomes [7], it remained in use until 1971 in the United States and until the early 1980s in some other countries. In 1971, in-utero exposure to DES was linked to the occurrence of vaginal clear cell adenocarcinoma in female offspring [8], which prompted the US Food and Drug Administration (FDA) to advise against its use in pregnancy [9]. Subsequently, other health effects, such as pregnancy complications and male genitourinary tract abnormalities, were also linked to in-utero DES exposure. DES is no longer commercially available for human use in North America.

DES remains the only firmly established transplacental carcinogen in humans. Because of this risk, it is important to continue to monitor exposed offspring and their mothers for long-term health effects. DES is also important as the model agent for endocrine disrupting chemicals and their effects on fetal development and adult health [10,11]. Aberrant DNA methylation has been proposed as a molecular mechanism whereby endocrine disruptors such as DES regulate developmental programming [12].


Breast cancer risk — There appears to be a slightly increased incidence of breast cancer among women who were prescribed DES during pregnancy (DES mothers) [13-18]. The largest and most comprehensive study on this topic compared long-term cancer risk in a database of 3844 women prescribed DES during pregnancy to an unexposed comparison group of 3716 women [14]. Women who took DES had a small increased risk of breast cancer (relative risk [RR] 1.27, 95% CI 1.07-1.52); looked at in another way, their lifetime risk of breast cancer increased from 1 in 8 (about 12 percent) to 1 in 6 (about 17 percent). There was no evidence of an interaction between the use of postmenopausal hormone therapy and DES in relation to breast cancer risk, and the risk did not increase over time. The higher risk did not appear to be due to inherent characteristics of the women who were given DES (ie, women with pregnancy problems) [16].

Other cancers — Women who were prescribed DES during pregnancy are not at increased risk of ovarian or endometrial cancer [13-18].


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