However, they also noted that the importance of the activities requires further study in animal models at pharmacologically relevant doses.DES has been identified as an antagonist of all three isotypes of the estrogen-related receptors (ERRs), the ERRα, ERRβ, and ERRγ. Half-maximal inhibition occurs at a concentration of about 1 μM. Pharmacokinetics
DES is well-absorbed with oral administration. With an oral dosage of 1 mg/day DES, plasma levels of DES at 20 hours following the last dose ranged between 0.9 and 1.9 ng/mL (3.4 to 7.1 nmol/L). Sublingual administration of DES appears to have about the same estrogenic potency of oral DES in women. Intrauterine DES has been studied for the treatment of uterine hypoplasia. Oral DES is thought to have about 17 to 50% of the clinical estrogenic potency of DES by injection.The distribution half-life of DES is 80 minutes. It has no affinity for SHBG or corticosteroid-binding globulin, and hence is not bound to these proteins in the circulation. The plasma protein binding of DES is greater than 95%.Hydroxylation of the aromatic rings of DES and subsequent conjugation of the ethyl side chains accounts for 80 to 90% of DES metabolism, while oxidation accounts for the remaining 10 to 20% and is dominated by conjugation reactions. Conjugation of DES consists of glucuronidation, while oxidation includes dehydrogenation into (Z,Z)-dienestrol. The medication is also known to produce paroxypropione as a metabolite. DES produces transient quinone-like reactive intermediates that cause cellular and genetic damage, which may help to explain the known carcinogenic effects of DES in humans.
Clinical use
DES was first marketed for medical use in 1939. It was approved by the United States Food and Drug Administration (FDA) on September 19, 1941, in tablets up to 5 mg for four 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. From its very inception, the drug was highly controversial.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. DES was the first cancer drug.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.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 after oophorectomy. In the 1940s, DES was used off-label to prevent adverse pregnancy outcomes in women with a history of miscarriage. On July 1, 1947, the FDA approved the use of DES for this indication. The first such approval was granted to Bristol-Myers Squibb, allowing use of 25 mg (and later 100 mg) tablets of DES during pregnancy. Approvals were granted to other pharmaceutical companies later in the same year.