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Diethylstilbestrol (DES) is a drug, an orally active synthetic nonsteroidal estrogen that was first synthesized in 1938. In 1971 it was found to be a teratogen when given to pregnant women.
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, based on a formulation of Wilfrid Lawson at the Courtand Institute of Biochemistry, led by Sir Edward Charles Dodds at Middlesex Hospital Medical School of the University College London of the University of London, and a report of its synthesis was published in Nature on February 5, 1938.[1][2][3]
Unlike the orally active synthetic steroidal estrogen ethinyl estradiol (first synthesized in 1938 and patented by the German pharmaceutical company Schering), DES was first synthesized by English university research funded by the MRC who had a policy against patenting drugs discovered using public funds. Because DES was not patented, was inexpensive to synthesize from coal tar, and was produced by over 300 pharmaceutical companies, its price was kept low from the beginning by competition.
DES (in tablets up to 5 mg) was approved by the FDA on September 19, 1941 for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement.[3] The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available.
In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found DES to be the first effective drug for treatment of metastatic prostate cancer.[4][5] Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over forty years, until the (much more expensive) GnRH agonist leuprolide was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.[6]
From the 1940s until the late 1980s, DES was FDA-approved as estrogen-replacement therapy for estrogen deficiency states such as ovarian dysgenesis, premature ovarian failure, and post-oophorectomy.
It was first prescribed by physicians to prevent miscarriages (in women who had had previous miscarriages) in the 1940s as an off-label use. On July 1, 1947, the FDA approved the first supplemental new drug application (by Squibb) adding prevention of miscarriage as an indication and approved 25 mg (and later 100 mg) tablets of DES for this indication, and approved applications of several other pharmaceutical companies in the second half of 1947.[7] The recommended regimen started at 5 mg per day in the 7th and 8th week of pregnancy (from first day of last menstrual period), increasing every other week by 5 mg per day through the 14th week, then increasing 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.[8] DES was originally considered effective and safe for both the pregnant woman and the developing baby. A double-blind study of pregnant women (unselected for history of miscarriage) was not published until six years after DES received FDA approval for prevention of miscarriage.[9] Even though it found that pregnant women given DES had just as many miscarriages and premature deliveries as the control group, DES continued to be aggressively marketed and routinely prescribed (though in decreasing frequency—sales peaked in 1953 and by the late 1960s six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage).[7][10]
In the United States, an estimated 5-10 million persons were exposed to DES during 1941-1971, including women who were prescribed DES while pregnant and the female and male children born of these pregnancies.
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