Synthesis DES was first synthesized in early 1938 by Leon Golberg, then a graduate student of
Sir Robert Robinson at the
Dyson Perrins Laboratory at the
University of Oxford. Golberg's research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by
Sir Edward Charles Dodds at
Middlesex Hospital Medical School now part of
University College London). A report of its synthesis was published in
Nature on 5 February 1938. DES research was funded by the
UK Medical Research Council (MRC), which had a policy against patenting drugs discovered using public funds. Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.
Clinical use DES was first marketed for medical use in 1939. Thorough toxicological studies were not performed on the drug before it was dispensed to women in non-standardized doses worldwide. In 1941,
Charles Huggins and Clarence Hodges at the
University of Chicago found
estradiol benzoate and DES to be the first effective drugs for the treatment of metastatic
prostate cancer.
Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the
GnRH agonist leuprorelin was found to have efficacy similar to DES without estrogenic effects and was approved in 1985. The recommended regimen started at 5 mg per day in the seventh and eighth weeks of pregnancy (from first day of last menstrual period), increased every other week by 5 mg per day through the 14th week, and then increased every week by 5 mg per day from 25 mg per day in the 15th week to 125 mg per day in the 35th week of pregnancy. DES was originally considered effective and safe for both the
pregnant woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953. In the early 1950s, a
double-blind clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES. The study showed no benefit of taking DES during pregnancy; adverse pregnancy outcomes were not reduced in the women who were given DES. By the late 1960s, six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage. Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes, DES continued to be given to pregnant women through the 1960s. In 1971, a report published in the
New England Journal of Medicine showed a probable link between DES and
vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug
in utero. Later in the same year, the FDA sent an FDA Drug Bulletin to all U.S. physicians advising against the use of DES in pregnant women. The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use. On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975. DES was also used in other countries, most notably France, the Netherlands, and Great Britain. In 1960, DES was found to be more effective than
androgens in the treatment of advanced
breast cancer in postmenopausal women. DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved
tamoxifen, a
selective estrogen receptor modulator with efficacy similar to DES but fewer side effects. Several sources from medical literature in the 1970s and 1980s indicate that DES was used as a component of
hormone therapy for
transgender women. In 1973, in an attempt to restrict
off-label use of DES as a
postcoital contraceptive (which had become prevalent at many university health services following publication of an influential study in 1971 in
JAMA) to emergency situations such as rape, an
FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES. In 1975, the FDA said it had not actually given (and never did give) approval to any manufacturer to market DES as a postcoital contraceptive, but would approve that indication for emergency situations such as rape or incest if a manufacturer provided patient labeling and special packaging as set out in a FDA final rule published in 1975. To discourage off-label use of DES as a postcoital contraceptive, the FDA in 1975 removed DES 25 mg tablets from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications changed to state: "This drug product should not be used as a postcoital contraceptive" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label. In the 1980s, off-label use of the
Yuzpe regimen of certain regular
combined oral contraceptive pills superseded off-label use of DES as a postcoital contraceptive. In 1978, the FDA removed postpartum
lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens. In the 1990s, the only approved indications for DES were treatment of advanced prostate cancer and treatment of advanced breast cancer in postmenopausal women. The last remaining U.S. manufacturer of DES,
Eli Lilly, stopped making and marketing it in 1997.
Trials Diethylstilbestrol has been used countless times in studies on rats. Once it was discovered that DES was causing vaginal cancer, experiments began on both male and female rats. Many of these male rats were injected with DES while other male rats were injected with olive oil as a control group. Some rats who were given DES died before delivering their pup. DES usage during pregnancy was common, and there have been known to be toxic and adverse effects to the hormone therapy. "Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, <2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10 000." Initial studies provided to the FDA were mostly conducted on laboratory animals. These preliminary tests showed that DES could cause sexual differentiation in offspring that only emerged following sexual maturity. The FDA was concerned by these findings with
Walter Campbell, who was
Commissioner of the FDA at the time, arguing that the agency should be cautious approving drugs without evidence that they wouldn't cause harm. As a result, DES then began to see a withdraw from the US market starting in 1972 and in the European market starting in 1978, but the FDA still did not withdraw its approval for the use of DES in humans. DES was classified as a Group 1 carcinogen by the International Agency for Research on Cancer. After classification as a carcinogen, DES had its FDA approval withdrawn in 2000.
Medical ethics Medical ethics in regard to the approval and use of diethylstilbestrol have been dismissed because of the actions of the FDA and pharmaceutical companies that were making DES at the time of its use. The Vice President of the American Drug Manufacturers Association, Carson Frailey, was employed by drug companies creating DES in order to help get it approved by the
Food and Drug Administration (FDA). Nancy Langston, the author of The Retreat from Precaution: Regulating Diethylstilbestrol (DES), Endocrine Disruptors, and Environmental Health, states that "Frailey persuaded fifty-four doctors from around the country to write to the FDA, describing their clinical experiences with a total of more than five thousand patients. Only four of these fifty-four doctors felt that DES should not be approved, and the result was that, against the concerns of many of the FDA medical staff, the FDA's drug chief Theodore Klumpp recommended that the FDA approve DES." This excerpt describes how DES was unethically approved and shows that the motivation behind its approval was for the benefit of drug companies rather than the people who were going to use the drug. This approval of DES violates the values of medical ethics,
autonomy,
non-maleficence,
beneficence, and
justice as there was little thought put into how DES would affect its users. The decisions made by the FDA leaders to approve DES without further study and convince doctors to dissimulate their opinions on the use of DES is unethical. Once DES was approved for public consumption the "warnings [for DES were] made available only on a separate circular that patients would not see. Doctors could get this warning circular only by writing to the drug companies and requesting it. Letters between companies and FDA regulators reveal that both groups feared that if a woman ever saw how many potential risks DES might present, she might refuse to take the drug—or else she might sue the company and the prescribing doctors if she did get cancer or liver damage after taking the drug." The plaintiffs had asked the courts to certify their case as a class action but were declined by the courts. However, the courts issued an opinion that their case had merit. The court held that Eli Lilly had a duty to notify about the risks of DES once they became aware of them or should have become aware of them. The advocacy group
DES Action USA helped provide information and support for DES-exposed persons engaged in lawsuits. ==Society and culture==