Diethylstilbestrol

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Diethylstilbestrol
Systematic (IUPAC) name
4-[(E)-4-(4-hydroxyphenyl)hex-3-en-3-yl]phenol
Identifiers
CAS number 56-53-1
ATC code  ?
PubChem 448537
DrugBank APRD00920
Chemical data
Formula  ?
Mol. mass 268.35 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism Hepatic
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

X

Legal status
Routes IV, oral

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 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.[1][2][3]

Contents

[edit] 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.<ref name=dodds1>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. </ref><ref name=dodds2>Template:Cite book</ref><ref name=meyers>Template:Cite book</ref>

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.

[edit] Clinical use

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.<ref name=meyers/> 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.<ref>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. </ref><ref> "Prostate cancer yields to a drug" (Dec 15, 1943). The New York Times: 29. </ref> 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.<ref>The Leuprolide Study Group (1984). "Leuprolide versus diethylstilbestrol for metastatic prostate cancer". N Engl J Med 311 (20): 1281–6. PMID 6436700. </ref>

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.<ref name=dutton>Template:Cite book</ref> 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.<ref name=pdr1961>Template:Cite book</ref> 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.<ref name=dieckmann>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. </ref> 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).<ref name=dutton/><ref name=apfel>Template:Cite book</ref>

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.<ref>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. </ref> 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.<ref>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. </ref>

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.<ref>Kuchera LK (1971). "Postcoital contraception with diethylstilbestrol". JAMA 218 (4): 562–3. doi:10.1001/jama.218.4.562. PMID 5171004. </ref><ref>FDA (May 1973). "Postcoital diethylstilbestrol". FDA Drug Bull. </ref> 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.<ref>FDA (1975). "Diethylstilbestrol as posticoital oral contraceptive; patient labeling". Fed Regist 40 (25): 5451–5. </ref> 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.<ref name=des25mg>FDA (1975). "Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications". Fed Regist 40 (25): 5384. </ref><ref>FDA (1975). "Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice". Fed Regist 40 (39): 8242. </ref> 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.<ref>Template:Cite book</ref>

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens.<ref>FDA (1978). "Estrogens for postpartum breast engorgement". Fed Regist 43 (206): 49564–7. </ref>

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.

[edit] 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.<ref name=herbst>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. </ref>

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.<ref name=fr1971>FDA (1971). "Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation". Fed Regist 36 (217): 21537–8. </ref> On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975.<ref name=des25mg/> 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).Template:Fact

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.

[edit] First generation

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

[edit] 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. <ref>(Hatch, 1998)</ref>
  • Some studies suggest that otherwise-male children exposed to DES before birth may be more likely to be transsexual woman than otherwise-male children who have not been exposed.<ref>"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)</ref>

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.

[edit] 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<ref>(J Pediatr Hematol Oncol 2003; 25:635-636.)</ref> 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.

[edit] 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.

[edit] 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."<ref>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.</ref>

An article in The Epoch Times states that DES is still used in PR China, especially in the rearing of Chinese mitten crab from Yangcheng Lake<ref>(Article in Chinese</ref>

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.

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.

In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women.[11] 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.[12]

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.[13][14] 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.[15] 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.[16][17] 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.[18]

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens.[19]

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.[20]

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.[21] On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975.[16] 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).[citation needed]

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.

[edit] First generation 

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

[edit] 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 epididymal cysts and auto-immune disorders.[citation needed] Diethylstilbestrol can also cause feminisation of the male foetus, as DES undergoes metabolic epoxidation, and the epoxide product has affinity towards the estrogen receptors.[citation needed] 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[22] although a followup study showed the risk, though present, to be much lesser. [23]

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.

[edit] 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.) 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.

[edit] 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.

[edit] External links

[edit] 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."[24]

[edit] 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" (Dec 15, 1943). The New York Times: p. 29. 
  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.  (1961) Physicians' desk reference to pharmaceutical specialties and biologicals, 15th ed., Oradell NJ: Medical Economics, 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.  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. 
 12. 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. 
 13.  Kuchera LK (1971). "Postcoital contraception with diethylstilbestrol". JAMA 218 (4): 562–3. doi:10.1001/jama.218.4.562. PMID 5171004. 
 14.  FDA (May 1973). "Postcoital diethylstilbestrol". FDA Drug Bull. 
 15. FDA (1975). "Diethylstilbestrol as posticoital oral contraceptive; patient labeling". Fed Regist 40 (25): 5451–5. 
 16.  a b FDA (1975). "Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications". Fed Regist 40 (25): 5384. 
 17.  FDA (1975). "Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice". Fed Regist 40 (39): 8242. 
 18.  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. 
 19. FDA (1978). "Estrogens for postpartum breast engorgement". Fed Regist 43 (206): 49564–7. 
 20.  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. 
 21. FDA (1971). "Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation". Fed Regist 36 (217): 21537–8. 
 22.  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. Retrieved on 2007-04-24. 
 23.  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. Retrieved on 2007-04-24. 
 24. 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.

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