Diethylstilbestrol (DES) Pregnancy Treatment: A Promising Widely Used Therapy with Unintended Adverse Consequences

Abstract

Diethylstilbestrol (DES) was first synthesized in 1938 and was the first orally active nonsteroidal estrogen that could be used for human therapy [1]. At that time, endocrinology was in its infancy and this discovery was a unique and great advance. Recurrent pregnancy loss was a serious medical problem then as it is now. It was believed the problems were due to a faulty hormonal environment of the fetal-placental unit, rather than primarily to genetic causes, as we have subsequently learned. There were studies at that time indicating that compromised pregnancies had a deficient output of the hormone progesterone, and further studies conducted in the late 1940s in Boston using very crude measuring techniques suggested that this deficiency could be corrected by administering DES to the mother, which would then lead to a healthy pregnancy. These studies led to the widespread usage of the drug to prevent pregnancy loss [2][3][4].The initial examination of the newborns born to mothers treated with DES during pregnancy showed no abnormalities (C. Smith, personal communication). The treatment, however, was controversial. (A unique double-blind study conducted at the University of Chicago in the early 1950s failed to show any improved pregnancy outcome with DES therapy [5]. This study, while negative, was conducted on a healthy pregnant population, which was different than the Boston Study, which was conducted on a high-risk population with a history of bleeding in pregnancy or multiple pregnancy losses.) An additional problem is that the hormone assays in the Boston Study were later found to be faulty and not to actually measure progesterone (Louis L. Engel, PhD, personal communication). It is believed that DES continued to be heavily used in the 1960s, and it has been estimated that 2 to 4 million women in the United States took DES during pregnancy [6].Then, in the late 1960s, eight extraordinarily rare cases of clear cell adenocarcinoma (CCA) of the vagina were diagnosed and treated in women in their teens and early 20s in the Boston area [7]. No such cluster of cases in young patients had ever been seen previously. CCA of the vagina was known to be a cancer that rarely occurred even in older women. In an effort to understand the cause of this cluster, a case-control study was conducted at the Massachusetts General Hospital in 1971 that linked the appearance of these cancers to the patients' mothers having been treated with DES for pregnancy

Reproductive and hormonal risk factors of breast cancer: a historical perspective

“…The first synthesized estrogen, diethylstilbestrol (DES), was discovered in 1938 and was enthusiastically received, especially by doctors who used the drug to alleviate postmenopausal symptoms, to treat gynecologic bleeding disorders, and as palliative treatment for advanced prostate cancer 36. Gynecologists also prescribed DES to prevent pregnancy complications such as preeclampsia, premature delivery, abortion, and intrauterine death 37…”

“…This coincided with the concerns about other drugs, especially thalidomide. In addition, DES had shown no beneficial effects on pregnancy complications, and the results of a case–control study published in 1971 suggested that vaginal cancer was more frequent in daughters of women who had been treated with DES in pregnancy 36. Subsequent studies in the 1980s until the early 2000s suggested that DES may increase the risk of breast cancer both in women who took DES in pregnancy and in their daughters who were exposed to DES in utero 45,46…”