Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen which was previously used clinically to support pregnancy, has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy and in their offspring.
First generation
An estimated 3 million pregnant women in the USA were prescribed DES from 1941 through 1971. DES was also widely prescribed to women in Canada, the UK, Europe, Australia, and New Zealand during a similar period. Women who were prescribed DES during pregnancy have been shown to have a modestly increased risk of breast cancer and breast cancer mortality.
Second generation
DES daughters
DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. In 1971, the New England Journal of Medicine published a report showing that seven of eight girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES. Subsequent studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES. As a consequence of this evidence, DES is considered an established human carcinogen. DES was one of the first transplacental carcinogens discovered in humans, meaning a toxin could cross the placenta and harm the fetus. It had originally been believed that the placenta protected the developing fetus but it is now known that is not true. Daughters exposed to DES in utero may also have an increased risk of moderate to severe cervical squamous cell dysplasia and an increased risk of breast cancer.
In addition to its carcinogenic properties, DES is a known teratogen, an agent capable of causing malformations in daughters and sons who were exposed in utero. DES-exposed daughters are at an increased risk of abnormalities of the reproductive tract, including vaginal epithelial changes such as vaginal adenosis (which means a type of cell normally found in the uterus, columnar cells, are also present in the vagina), an increased cervical transformation zone, and uterine abnormalities, such as T-shaped uterus. These anomalies contribute to an increased risk of infertility and adverse pregnancy outcomes in prenatally DES-exposed daughters. The most recent published research on DES daughters' adverse health outcomes documented by the U.S. National Cancer Institute (NCI) appears in the October 6, 2011 issue of the New England Journal of Medicine under the authorship of RN Hoover et al., and lists these adverse effects and risk factors: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5%; spontaneous abortion, 50.3% vs. 38.6%; preterm delivery, 53.3% vs. 17.8%; loss of second-trimester pregnancy, 16.4% vs. 1.7%; ectopic pregnancy, 14.6% vs. 2.9%; preeclampsia, 26.4% vs. 13.7%; stillbirth, 8.9% vs. 2.6%; early menopause, 5.1% vs. 1.7%; grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4%; and breast cancer at 40 years of age or older, 3.9% vs. 2.2%. Daughters with prenatal exposure to DES may also have an increased risk of uterine fibroids, and incompetent cervix in adulthood.
Studies of DES daughters have not found a link between in utero exposure to DES and autoimmune diseases.
In an animal model designed to study environmental estrogens, DES turned out to be an obesogen capable of causing adult weight gain in female mice which had been exposed to DES during neonatal development. The excess weight gain was not apparent at birth or in infancy, but occurred in adulthood.
DES sons
Initially, fewer studies documented risks of prenatal exposure to DES on males (referred to as "DES sons"). In the 1970s and early 1980s, studies published on prenatally DES-exposed males investigated increased risk of testicular cancer, infertility and urogenital abnormalities in development, such as cryptorchidism and hypospadias. Research published in the U.S. by Palmer et al. in 2009 further confirmed evidence of these findings. Additional research published in Finland in 2012 has further confirmed an increased risk of cryptorchidism among males exposed prenatally to DES.
The U.S. Centers for Disease Control (CDC) has acknowledged the link between DES exposure and noncancerous epididymal cysts.
The American Association of Clinical Endocrinologists (AACE) has documented that prenatal DES exposure in males is positively linked to a condition known as hypogonadism (low testosterone levels) that may require treatment with testosterone replacement therapy.