Diethylstilbestrol: Wikis

  
  

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

Diethylstilbestrol
Systematic (IUPAC) name
4,4'-(3E)-hex-3-ene-3,4-diyldiphenol
Identifiers
CAS number 56-53-1
ATC code G03CB02 G03CC05, L02AA01
PubChem 3054
DrugBank APRD00920
ChemSpider 395306
Chemical data
Formula C18H20O2 
Mol. mass 268.35 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Metabolism Hepatic
Therapeutic considerations
Pregnancy cat. X
Legal status
Routes IV, oral
 Yes check.svgY(what is this?)  (verify)

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.

Contents

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, 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]

DES was first synthesized by English university research funded by the MRC who had a policy against patenting drugs discovered using public funds.

Clinical use

DES (in tablets up to 5 mg) was approved by the United States Food and Drug Administration 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 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.

From the 1950s through the beginning of the 1970s, DES was prescribed to prepubescent girls to begin puberty and thus stop growth by closing growth plates in the bones. Despite its clear link to cancer, doctors continued to recommend the hormone for "excess height." [11]

In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women.[12] DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women for two decades, until the 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.[13]

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.[14][15] 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.[16] 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.[17][18] 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.[19]

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens.[20]

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.[21]

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.[22] On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975.[17]

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.

Prenatal exposure to DES is associated with increased incidence of fibroids in adulthood.[1]

First generation

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

Second generation

  • 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. [23]
  • A new study shows DES daughters as having a 2.5 fold increase in breast cancer after age 40.
  • DES daughters have an elevated risk of ectopic pregnancy, up to 3 times the risk of unexposed women[citation needed].
  • In 2002, a study indicated that maternal usage of DES resulted in a 20-fold increase in prevalence of hypospadias in their sons[24] although a followup study showed the risk, though present, to be much less.[25]
  • Some studies suggest that otherwise-male children exposed to DES before birth may be more likely to be transsexual women than otherwise-male children who have not been exposed.[26]

In the 1970s, the negative publicity surrounding the discovery of DES's long-term effects resulted in a huge wave of lawsuits in the United States against its manufacturers. These culminated in a landmark 1980 decision of the Supreme Court of California, Sindell v. Abbott Laboratories, in which the court imposed a rebuttable presumption of market share liability upon all DES manufacturers, proportional to their share of the market at the time the drug was consumed by the mother of a particular plaintiff.

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[27] suggested that the effect of DES might 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, small cell carcinoma of the ovary, 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 (1 mg) 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.

DES in food production

During the 1960s, DES was used as a growth hormone in the beef and poultry industry. It was later found to cause cancer and was "phased out in the late 1970s."[28] Its alleged continued illegal use in the beef industry is depicted in the novel My Year of Meats, by Ruth L. Ozeki.

References

  1. ^ Dodds EC, Goldberg L, Lawson W, Robinson R (February 5, 1938). "Estrogenic activity of certain synthetic compounds". Nature 141 (3562): 247–8. doi:10.1038/141247b0. 
  2. ^ Dodds EC (1957). Biochemical contributions to endocrinology; experiments in hormonal research. Stanford: Stanford University Press. OCLC 1483899. 
  3. ^ a b Meyers, Robert (1983). D.E.S., the bitter pill. New York: Seaview/Putnam. ISBN 0-399-31008-8. 
  4. ^ Huggins C, Hodges CV (1941). "Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate". Cancer Res 1 (4): 293–7. 
  5. ^ "Prostate cancer yields to a drug". The New York Times: 29. Dec 15, 1943. 
  6. ^ The Leuprolide Study Group (1984). "Leuprolide versus diethylstilbestrol for metastatic prostate cancer". N Engl J Med 311 (20): 1281–6. PMID 6436700. 
  7. ^ a b Dutton, Diana B. (1988). Worse than the disease: pitfalls of medical progress. Cambridge: Cambridge University Press. ISBN 0-521-34023-3. 
  8. ^ Physicians' desk reference to pharmaceutical specialties and biologicals (15th ed.). Oradell NJ: Medical Economics. 1961. p. 625. 
  9. ^ Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE (1953). "Does the administration of diethylstilbestrol during pregnancy have therapeutic value?". Am J Obstet Gynecol 66 (5): 1062–81. PMID 13104505. 
  10. ^ Apfel, Roberta J.; Fisher Susan M. (1984). To do no harm: DES and the dilemmas of modern medicine. New Haven: Yale University Press. ISBN 0-300-03192-0. 
  11. ^ Zuger, Abigail, M.D. (July 27, 2009), At What Height, Happiness? A Medical Tale 
  12. ^ Council on Drugs (1960). "Androgens and estrogens in the treatment of disseminated mammary carcinoma: retrospective study of nine hundred forty-four patients". JAMA 172 (12): 1271–83. 
  13. ^ Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S (1984). "Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer". N Engl J Med 304 (1): 16–21. PMID 7001242. 
  14. ^ Kuchera LK (1971). "Postcoital contraception with diethylstilbestrol". JAMA 218 (4): 562–3. doi:10.1001/jama.218.4.562. PMID 5171004. 
  15. ^ FDA (May 1973). "Postcoital diethylstilbestrol". FDA Drug Bull. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1455105&blobtype=pdf. 
  16. ^ FDA (1975). "Diethylstilbestrol as posticoital oral contraceptive; patient labeling". Fed Regist 40 (25): 5451–5. 
  17. ^ a b FDA (1975). "Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications". Fed Regist 40 (25): 5384. 
  18. ^ FDA (1975). "Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice". Fed Regist 40 (39): 8242. 
  19. ^ Hatcher, Robert A.; Stewart, Gary K., Stewart, Felicia; Guest, Felicia; Josephs, Nancy; Dale, Janet (1982). Contraceptive Technology 1982-1983. New York: Irvington Publishers. pp. 152–7. ISBN 0-829-00705-9. 
  20. ^ FDA (1978). "Estrogens for postpartum breast engorgement". Fed Regist 43 (206): 49564–7. 
  21. ^ Herbst AL, Ulfelder H, Poskanzer DC (1971). "Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women". N Engl J Med 284 (15): 878–81. PMID 5549830. 
  22. ^ FDA (1971). "Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation". Fed Regist 36 (217): 21537–8. 
  23. ^ (Hatch, 1998)
  24. ^ Klip, H.; J. Verloop et al. (March 2002). "Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study". The Lancet 359 (9312): 1081–1082. doi:10.1016/S0140-6736(02)08126-6. PMID 11943257. 
  25. ^ Brouwers, MM.; WF. Feitz et al. (March 2006). "Hypospadias: a transgenerational effect of diethylstilbestrol?". Hum. Reprod. 21 (3): 666–669. doi:10.1093/humrep/dei398. PMID 16293648. 
  26. ^ "The Biology of Human Psychosexual Differentiation" by L. Gooren (Hormones and Behavior 50 (2006) 589-601), and "The Endocrinology of Transsexualism : a review and commentary" by L. Gooren (Psychoneuroendocrinology 15(1), 3-14)
  27. ^ (J Pediatr Hematol Oncol 2003; 25:635-636.)
  28. ^ Gandhi, Renu and Suzanne Snedeker. "Consumer Concerns About Hormones in Food." Cornell University Program on Breast Cancer and Environmental Risk Factors Fact Sheet #37(2000): 2.

See also

External links

Other resources








Got something to say? Make a comment.
Your name
Your email address
Message