Diethylstilbestrol

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.

Synthesis
DES was first synthesized in early 1938 by Leon Goldberg, 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.

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.

Clinical use
DES (in tablets up to 5 mg) was approved by the FDA on September 19, 1941 for 4 indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement. 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. 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 with fewer side effects and was approved in 1985.

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. 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. 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. 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).

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.

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 for two decades, until the (much more expensive) selective estrogen receptor modulator tamoxifen was found to have efficacy similar to DES with fewer side effects and was approved at the end of 1977.

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, a 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 DES in 1997.

Associated health problems
On April 15, 1971, the New England Journal of Medicine published a report by three physicians at Massachusetts General Hospital on the association of DES therapy started during the first trimester of pregnancy by mothers of 7 of 8 girls and young women ages 14 to 22 diagnosed with adenocarcinoma of the vagina.

In November 1971, the FDA sent a FDA Drug Bulletin to all U.S. physicians advising them to stop prescribing DES to pregnant women because it was linked to a rare vaginal cancer in female offspring, and on November 10, 1971 ordered that prevention of miscarriage be removed from Indications and pregnancy be added to Contraindications in the physician prescribing information for DES. On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975. DES was, however, never banned and continued to be prescribed in the U.S. and other countries well beyond 1971 (until 1978 in most European countries and as late as 1994 in some third world countries).

More than 30 years of research have confirmed that DES is a teratogen, an agent that can cause malformations of an embryo or fetus. However, not all exposed persons will experience the following DES-related health problems.

First generation

 * Women prescribed DES while pregnant are at a modestly increased risk for breast cancer.

Second generation

 * A new study shows DES daughters as having a 2.5 fold increase in breast cancer after age 40.


 * Women exposed to DES before birth (in the womb), known as DES Daughters, are at an increased risk for clear cell adenocarcinoma (CCA) of the vagina and cervix, reproductive tract structural differences, pregnancy complications, infertility, and auto-immune disorders. Although DES Daughters appear to be at highest risk for clear cell cancer in their teens and early 20s, cases have been reported in DES Daughters in their 30s and 40s (Hatch, 1998).


 * Men exposed to DES before birth (in the womb), known as DES Sons, are at an increased risk for non-cancerous epidydmal cysts and auto-immune disorders.Diethylstilbestrol can also cause feminisation of the male foetus, as DES undergoes metabolic epoxidation, and the epoxide product has affinity towards the estrogen receptors. In some cases there are sons with only one testis or both abdominal. In 2002, a study indicated that maternal usage of DES resulted in a 20-fold increase in prevalence of hypospadias in their sons although a followup study showed the risk, though present, to be much lesser.

Researchers are still following the health of persons exposed to DES to determine whether other health problems occur as they grow older.

Third generation
Current research also looks at DES third generation. Third generation refers to the offspring of DES sons and daughters. There is not yet much information available, because the third generation is not old enough to fully manifest possible physiological effects of inherited DES exposure.

Third generation injuries are associated with preterm labor or deliveries resulting in premature birth and cerebral palsy, blindness or other neurological deficits or death of a child.

Another study (J Pediatr Hematol Oncol 2003; 25:635-636.) found DES to be transgenerational, meaning that the maternal grandmother had taken DES while pregnant but the mother did not experience any health problems associated with the DES exposure. This was realized when a rare tumor was discovered on a 15 year old girl.

DES for canines
DES has been very successful in treating female canine incontinence stemming from poor sphincter control. It is still available from compounding pharmacies, and at the low (1mg) dose, does not have the carcinogenic properties that were so problematic in humans. It is generally administered once a day for five days and then once every 4 to 7 days as needed.

Other Resources
Diethylstilbestrol Diéthylstilbestrol Dietilstilbestrolo Diëthylstilbestrol ジエチルスチルベストロール