Diethylstilbestrol (DES) Update: Recommendations for the Identification and Management of DES-Exposed Individuals

Barbara Hammes, CNM, MS, Cynthia J. Laitman, PhD

Disclosures

J Midwifery Womens Health. 2003;48(1) 

In This Article

History of DES

DES, the first orally absorbable estrogen, was developed in 1938 by E. Charles Dodds at the University of London.[16] The synthesis of DES inspired a flurry of scientific activity, and as one expert noted in a presentation on the topic, in the next 2 years alone, several hundred papers on the use of DES were published.[17] DES was approved by the Food and Drug Administration for use in the United States in 1940. Because no patent for the drug was ever claimed, many drug companies in the United States simultaneously applied for the right to manufacture DES. After the Food and Drug Administration established a generic formulation in 1941 by which all drug companies had to abide,[18] 287 drug companies in the United States alone, at one time or another, eventually manufactured DES or DES-related compounds.[19] Table 1 lists the names under which the drug was marketed.[20]

Paralleling the events surrounding the development of DES were the careers of two Harvard professors, husband and wife, the gynecologist and biochemist team of Drs. George and Olive Smith. They had observed that plasma levels of pregnanediol, the by-product of progesterone secreted in urine, fell before complications of late pregnancy set in. They theorized that if low endogenous levels of progesterone were threatening pregnancy, then exogenous estrogen would stimulate the body's production of progesterone, thereby saving the pregnancy. These physicians started administering naturally derived estrogen to high-risk pregnant women in 1938. They switched to DES when they observed DES was able to stimulate an unlimited production of progesterone. In 1948, Olive Smith published an article promoting DES as an "antimiscarriage agent."[21] The standard regimen began with 5 mg daily, increasing in 5-mg increments every 2 weeks throughout the pregnancy until doses reached as high as 150 mg daily. Although first promoted for high-risk pregnancies, DES was soon adopted as a sort of pregnancy super vitamin, "making healthy babies healthier," and was marketed in pills combined with vitamins (Figure 1).

The effectiveness of DES was tested in 1952 by Ferguson of Tulane University,[22] and 1 year later by Dieckmann at the University of Chicago. The Dieckmann study[23] was a seminal study, as the first controlled, double-blind trial of the effectiveness of DES as an antimiscarriage agent. Approximately 2,000 women attending the obstetric clinic for the University of Chicago Medical School were consecutively enrolled. Alternately, half received DES and half received the placebo. The women treated with DES actually had a slightly higher incidence of miscarriage than the placebo control group, although the difference was not statistically significant.[23] Despite these findings, DES continued to be prescribed for pregnancy preservation for 18 more years. By one estimate, two to four million women in the United States alone were given DES during pregnancy.[24]

DES was also used as an antilactation medication for postpartum women choosing not to breastfeed, as a morning-after type of contraception, and as a treatment for both breast and prostate cancer.[25] In animals, it was used as a feed additive and as an injectable in poultry and cattle to stimulate growth before slaughter.[26] In 1959, the Food and Drug Administration banned the drug in poultry after a cluster of cases of gynecomastia and sterility was noted in male workers in poultry-processing facilities.[27] Thesecases were traced to DES implants in the chicken necks that were taken home by poultry workers to cook and eat. It took another 20 years to ban the drug's use in cattle. Even after it was banned, cattlemen were able to stockpile and continue using DES in their herds until the 1980s.[28,29]

In 1962, the Food and Drug Administration, with the help of the National Academy of Sciences, established a new criterion for all pharmaceuticals; in addition to safety, drug manufacturers now had to demonstrate effectiveness for the purpose intended.[30] Drugs that could not meet the new standard of proved effectiveness were to be removed from the market. Despite that official intention and the fact that DES had already been proved to be ineffective in preventing miscarriages,[23] DES continued to be manufactured and prescribed as antimiscarriage therapy.

In 1971, Herbst et al.[31] published an article in the New England Journal of Medicine reporting seven cases of a rare vaginal clear cell adenocarcinoma in adolescent girls and young women, an unprecedented medical occurrence. All seven women were exposed to DES prenatally. The Registry for Research on Hormonal Transplacental Carcinogenesis was then established by Dr. Arthur L. Herbst and colleagues from Harvard and subsequently relocated to the University of Chicago. The goal of the registry is to collect information on all cases of cervical and vaginal clear cell carcinoma arising in women born after 1948.

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