Teratogen update: Carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero

Abstract

Exposure of the human fetus to physician-prescribed diethylstilbestrol and other synthetic estrogens (collectively referred to as "DES") led to an important iatrogenic epidemic. In the United States alone, at least four million fetuses and their mothers had a substantial exposure to these estrogens now known to be mild carcinogens and potent teratogens. Mothers exposed to DES may have a somewhat higher risk of breast cancer than women who were not exposed. The sequelae of in utero exposure of daughters include clear cell adenocarcinoma of the vagina and cervix, various gross anomalies of the genital tract that are associated with adverse outcomes of pregnancy, vaginal adenosis and other vaginal epithelial changes, and other possible health effects that have not yet been fully evaluated. Among sons exposed in utero to DES, no increase in the incidence of any cancer has been reported, but several anomalies of the genital tract have been described, and it is possible that some social behaviors are modified. Although the grandchildren of the DES-exposed daughters and sons have not been shown to have any abnormalities, some of them have been the products of short gestations. Future research, being funded by the National Cancer Institute, will permit monitoring of the DES-exposed population to determine whether any other abnormalities will become apparent in them.

Exposure assessment for endocrine disruptors: some considerations in the design of studies.

“…Turner syndrome occurs in individuals with XY chromosomes due to mutation of the androgen receptor gene; this results in the development of female external genitalia. Developmental abnormalities due to exposure to endocrine-disrupting drugs (e.g., DES) are also well documented (George and Wilson 1994;Mittendorf 1995;Swan and vom Saal 2001). The importance of small changes in the concentration of endocrine-signaling molecules during critical periods in development has been studied extensively in laboratory animals and wildlife (Colborn et al 1993;Fry 1995;Guillette et al 1995;vom Saal 1989;vom Saal et al 1997).…”

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure

“…This potent synthetic estrogen was administered to women as an anti-abortive therapy between the years 1948 and 1971 in the US, Europe and Australia. Tragically, this therapy was continued long after it was shown to be ineffective, and was finally stopped in the early 1970's when a rare pathology, clear cell adenocarcinoma of the vagina [10,11], as well as other abnormalities of the uterus, oviduct and cervix were diagnosed in young women that had been exposed to DES in utero [12,13]. These women are now reaching the age at which breast cancer becomes more prevalent.…”

A case of clear cell adenocarcinoma in the uterine cervix of 52-year-old virgin

“…The primary treatment of early disease usually involved radical surgery with pelvic±para-aortic lymphadenectomy, with outcomes comparable to other types of cervical adenocarcinoma [14,15]. Important parameters for the determination of prognosis of CCAC patients are stage, tumor size, growth pattern, nuclear atypia, and mitotic activity [1,4,5]. In the current study, an unfavorable prognosis corresponded with high stage, large tumor size, high grade of nuclear atypia, and high mitotic activity.…”

“…The former group includes most of DESexposed women, and the latter is constituted mostly by those without a history of DES exposure [3]. DES has been considered as a teratogen which crosses placental barrier [4]. During 4th and 18th weeks of normal development, the Müllerian ducts of the embryo extend caudally and fuse to form a solid structure, the uterovaginal primordium.…”