Diethylstilbestrol

Diethylstilbestrol
Systematic (IUPAC) name
4,4'-(3E)-hex-3-ene-3,4-diyldiphenol; (E)-11,12-Diethyl-4,13-stilbenediol
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • X
Routes of
administration		 IV, oral
Identifiers
CAS Number 56-53-1 YesY
ATC code G03CB02 (WHO) G03CC05 (WHO), L02AA01 (WHO)
PubChem CID 448537
IUPHAR/BPS 2801
DrugBank DB00255 YesY
ChemSpider 395306 YesY
UNII 731DCA35BT YesY
KEGG D00577 YesY
ChEBI CHEBI:41922 YesY
ChEMBL CHEMBL411 YesY
Chemical data
Formula C18H20O2
Molar mass 268.35 g/mol
  (verify)

Diethylstilbestrol (DES) (INN, USAN, BAN), also known formerly and inappropriately as stilboestrol (BAN), is a synthetic, non-steroidal estrogen of the stilbestrol group that was first synthesized in 1938.[1] It is also classified as an endocrine disruptor. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers. From about 1940 to 1971, DES was given to pregnant women in the mistaken belief it would reduce the risk of pregnancy complications and losses.

In 1971, DES was shown to cause clear cell carcinoma, a rare vaginal tumor in girls and women who had been exposed to this drug in utero. The United States Food and Drug Administration subsequently withdrew DES from use in pregnant women. Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed.[2] The United States National Cancer Institute recommends[3] women born to mothers who took DES undergo special medical exams on a regular basis to screen for complications as a result of the drug. Individuals who were exposed to DES during their mothers' pregnancies are commonly referred to as "DES daughters" and "DES sons".

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. Golberg's research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by Sir Edward Charles Dodds at Middlesex Hospital Medical School now part of University College London). A report of its synthesis was published in Nature on 5 February 1938.[4][5][6]

DES research was funded by the UK Medical Research Council (MRC), which had a policy against patenting drugs discovered using public funds. Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.

Clinical use

DES (in tablets up to 5 mg) was approved by the United States Food and Drug Administration (FDA) on September 19, 1941 for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement.[6] The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available. From its very inception, the drug was highly controversial.[7][8]

In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found DES to be the first effective drug for the treatment of metastatic prostate cancer.[9][10] Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the GnRH agonist leuprolide was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.[11]

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.[12] The recommended regimen started at 5 mg per day in the seventh and eighth weeks of pregnancy (from first day of last menstrual period), increased every other week by 5 mg per day through the 14th week, and then increased 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.[13] DES was originally considered effective and safe for both the pregnant woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953.

In the early 1950s, a double-blind clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES.[14] The study showed no benefit of taking DES during pregnancy; adverse pregnancy outcomes were not reduced in the women who were given DES. By the late 1960s, six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage.[12][15]

Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes, DES continued to be given to pregnant women through the 1960s. In 1971, a report published in the New England Journal of Medicine showed a probable link between DES and vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug in utero. Later in the same year, the FDA sent an FDA Drug Bulletin to all U.S. physicians advising against the use of DES in pregnant women. The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use.[16] On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975.[17] The number of persons exposed to DES during pregnancy or in utero during 1940–1971 is unknown, but may be as high as 2 million in the United States. DES was also used in other countries, most notably France, the Netherlands, and Great Britain.

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".[18]

In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women.[19] DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved tamoxifen, a selective estrogen receptor modulator with efficacy similar to DES but fewer side effects.[20]

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.[21] 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.[22] 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][23] 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.[24]

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens.[25] 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 it in 1997.

Associated health problems

First generation

An estimated 3 million pregnant women in the USA were prescribed DES from 1941 through 1971.[26][27] DES was also widely prescribed to women in Canada, the UK, Europe, Australia, and New Zealand during a similar period. Women who were prescribed DES during pregnancy have been shown to have a modestly increased risk of breast cancer and breast cancer mortality.[28]

Second generation

DES daughters

DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. In 1971, the New England Journal of Medicine published a report showing that seven of eight girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES.[29] Subsequent studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES. As a consequence of this evidence, DES is considered an established human carcinogen. DES was one of the first transplacental carcinogens discovered in humans, meaning a toxin could cross the placenta and harm the fetus. It had originally been believed that the placenta protected the developing fetus but it is now known that is not true. Daughters exposed to DES in utero may also have an increased risk of moderate to severe cervical squamous cell dysplasia and an increased risk of breast cancer.[30]

In addition to its carcinogenic properties, DES is a known teratogen, an agent capable of causing malformations in daughters and sons who were exposed in utero. DES-exposed daughters are at an increased risk of abnormalities of the reproductive tract, including vaginal epithelial changes such as vaginal adenosis (which means a type of cell normally found in the uterus, columnar cells, are also present in the vagina), an increased cervical transformation zone, and uterine abnormalities, such as T-shaped uterus. These anomalies contribute to an increased risk of infertility and adverse pregnancy outcomes in prenatally DES-exposed daughters. The most recent published research on DES daughters' adverse health outcomes documented by the U.S. National Cancer Institute (NCI) appears in the October 6, 2011 issue of the New England Journal of Medicine under the authorship of RN Hoover et al., and lists these adverse effects and risk factors: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5%; spontaneous abortion, 50.3% vs. 38.6%; preterm delivery, 53.3% vs. 17.8%; loss of second-trimester pregnancy, 16.4% vs. 1.7%; ectopic pregnancy, 14.6% vs. 2.9%; preeclampsia, 26.4% vs. 13.7%; stillbirth, 8.9% vs. 2.6%; early menopause, 5.1% vs. 1.7%; grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4%; and breast cancer at 40 years of age or older, 3.9% vs. 2.2%.[31] Daughters with prenatal exposure to DES may also have an increased risk of uterine fibroids, and incompetent cervix in adulthood.[32]

At least one published study by researchers specializing in psycho-sexual development has determined there is a positive association between in-utero DES exposure among DES daughters and increased potential for a girl being homosexual or bisexual.[33] However, later studies have concluded that "no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior,"[34] and another found that "DES Daughters were slightly more likely than unexposed women to have ever been married and were less likely to report having had a same-sex sexual partner."[35] These studies contradict earlier studies indicating an inclination towards female attraction in DES daughters, as well as no indication for increased prevalence of gender-atypical behavior.

Studies of DES daughters have not found a link between in utero exposure to DES and autoimmune diseases.[36]

In an animal model designed to study environmental estrogens, DES turned out to be an obesogen capable of causing adult weight gain in female mice which had been exposed to DES during neonatal development. The excess weight gain was not apparent at birth or in infancy, but occurred in adulthood.[37][38]

DES sons

Initially, fewer studies documented risks of prenatal exposure to diethylstilbestrol on males (referred to as "DES sons"). In the 1970s and early 1980s, studies published on prenatally DES-exposed males investigated increased risk of testicular cancer, infertility and urogenital abnormalities in development, such as cryptorchidism and hypospadias.[39][40] Research published in the U.S. by Palmer et al. in 2009 further confirmed evidence of these findings.[41] Additional research published in Finland in 2012 has further confirmed an increased risk of cryptorchidism among males exposed prenatally to DES.[42]

The U.S. Centers for Disease Control (CDC) has acknowledged the link between diethylstilbestrol exposure and noncancerous epididymal cysts.[43]

The American Association of Clinical Endocrinologists (AACE) has documented that prenatal DES exposure in males is positively linked to a condition known as hypogonadism (low testosterone levels) that may require treatment with testosterone replacement therapy.[44]

Exposed males may have a greater likelihood of being left-handed than unexposed males.[45]

Research on DES sons has explored the long-standing question of whether prenatal exposure to DES in males may include sexual and gender-related behavioral effects and also intersex conditions. Dr. Scott Kerlin, a major DES researcher and founder of the DES Sons International Research Network in 1999, has documented for the past 16 years a high prevalence of individuals with confirmed prenatal DES exposure who self-identify as male-to-female transsexual, transgender, or have intersex conditions, and many individuals who report a history of experiencing difficulties with gender dysphoria.[46][47][48][49]

A large US study, in which recruitment was not dependent on health concerns, and in which DES exposure (or lack of exposure) was confirmed for all participants, found The OR (odds ratio) for exposed men having had a same-sex sexual partner was 1.3[35] for DES-exposed men compared to unexposed men. However, no research into gender identity issues was explored in this study.[35]

Various neurological changes occur after prenatal exposure of embryonic males to DES and other estrogenic endocrine disrupters. Animals that exhibited these structural neurological changes were also shown to demonstrate various gender-related behavioral changes (so-called "feminization of males"). Several published studies in the medical literature on psychoneuroendocrinology have examined the hypothesis that prenatal exposure to estrogens (including DES) may cause significant developmental impact on sexual differentiation of the brain, and on subsequent behavioral and gender identity development in exposed males and females.[50][51] There is significant evidence linking prenatal hormonal influences on gender identity and transsexual development.[52][53][54]

Psychological anomalies

Most of the initial research documenting the psychological effects of prenatal DES exposure was poorly conducted, often by mail card. Despite that, some more carefully conducted studies show a clear link to depression.[55][56], and a more recent French study asserts that there was an 83% increase in psychological disorders for offspring that was prenatally exposed to DES.[57]

Lawsuits

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.

A lawsuit was filed in Boston Federal Court by 53 DES daughters who say their breast cancers were the result of DES being prescribed to their mothers while pregnant with them. Their cases survived a Daubert hearing. In 2013, the Fecho sisters who initiated the breast cancer/DES link litigation agreed to an undisclosed settlement amount on the second day of trial. The remaining litigants have received various settlements.[58]

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 in the third generation. These are the children of men and women who were exposed to DES in utero; thus, they are also the grandchildren of women who were given DES during pregnancy. Studies of the third generation are important because DES might be associated with epigenetic changes, which involve changes to the way genes behave (not involving the DNA itself) that may be heritable from one generation to another. If epigenetic changes occur and are heritable, studies of the DES-exposed third generation have implications for the influence of environmental endocrine disruptors on human health and evolution.

Recent studies from the US National Cancer Institute (NCI) show that the daughters of women who were exposed in utero to DES may be less likely than the unexposed to have regular menstrual periods.[59] A possible increased risk of infertility in the older, third generation daughters was also noted. The NCI study provides limited evidence of an increased risk of birth defects in the sons or daughters of women who were exposed prenatally to DES. An increased risk of ovarian cancer in the daughters of women exposed in utero was observed, but it was based on three cases of almost 800, so the finding is considered preliminary and requires further study.

Some evidence suggests the sons of prenatally DES-exposed women might have an increased risk of hypospadias,[60][61] but other studies suggest the increase in risk might not be as great as once thought.[62]

Pharmacology

Pharmacodynamics

DES is a very potent agonist of the estrogen receptors.

Pharmacokinetics

DES produces paroxypropione as an active metabolite.[63]

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.[64] It is generally administered once a day for seven to ten days and then once every week as needed.

DES in food production

The greatest usage of DES was in the livestock industry, used in improve feed conversion in beef and poultry. During the 1960s, DES was used as a growth hormone in the beef and poultry industries. It was later found to cause cancer by 1971, but was not phased out until 1979.[65][66] When DES was discovered to be harmful to humans, it was moved to veterinary use.

In fiction

An account of DES's use in the beef industry is depicted in the novel My Year of Meats, by Ruth L. Ozeki.

It was also prescribed as a "cure" for homosexuality in Season 4, Episode 3 of BBC series Call the Midwife.

See also

References

  1. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 396–. ISBN 978-1-4757-2085-3.
  2. ↑ "DES Update: For Consumers". United States Department of Health and Human Services: Centers for Disease Control and Prevention. Retrieved 2011-06-30.
  3. ↑ "DES: Questions and Answers". FactSheet. National Cancer Institute. Retrieved 2011-06-30.
  4. ↑ Dodds EC, Goldberg L, Lawson W, Robinson R (1938). "Estrogenic activity of certain synthetic compounds". Nature 141 (3562): 247–8. doi:10.1038/141247b0.
  5. ↑ Dodds EC (1957). Biochemical contributions to endocrinology; experiments in hormonal research. Stanford: Stanford University Press. OCLC 1483899.
  6. 1 2 Meyers R (1983). D.E.S., the bitter pill. New York: Seaview/Putnam. ISBN 0-399-31008-8.
  7. ↑ Langston N (2010). Toxic bodies: Hormone disruptors and the legacy of DES. New Haven, CT: Yale University Press. ISBN 978-0-300-13607-4.
  8. ↑ Seaman B (2003). The greatest experiment ever performed on women: Exploding the estrogen myth. New York: Hyperion. ISBN 978-0-7868-6853-7.
  9. ↑ Huggins C, Hodges CV (1972). "Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate". CA Cancer J Clin 22 (4): 232–40. doi:10.3322/canjclin.22.4.232. PMID 4625049.
  10. ↑ "Prostate cancer yields to a drug". The New York Times: 29. 1943.
  11. ↑ The Leuprolide Study Group (1984). "Leuprolide versus diethylstilbestrol for metastatic prostate cancer". N. Engl. J. Med. 311 (20): 1281–6. doi:10.1056/NEJM198411153112004. PMID 6436700.
  12. 1 2 Dutton DB (1988). Worse than the disease: pitfalls of medical progress. Cambridge: Cambridge University Press. ISBN 0-521-34023-3.
  13. ↑ Physicians' desk reference to pharmaceutical specialties and biologicals (15th ed.). Oradell NJ: Medical Economics. 1961. p. 625. ISBN 0-00-093447-X.
  14. ↑ 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.
  15. ↑ Apfel R J, Fisher SM (1984). To do no harm: DES and the dilemmas of modern medicine. New Haven: Yale University Press. ISBN 0-300-03192-0.
  16. ↑ United States Food and Drug Administration (FDA) (1971). "Certain estrogens for oral or parenteral use. Drugs for human use; drug efficacy study implementation". Fed Regist 36 (217): 21537–8.; 36 FR 21537
  17. 1 2 FDA (1975). "Certain estrogens for oral use. Notice of withdrawal of approval of new drug applications". Fed Regist 40 (25): 5384.; 25 FR 5384
  18. ↑ Zuger A (2009-07-27). "At What Height, Happiness? A Medical Tale". The New York Times. NY Times.
  19. ↑ 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. doi:10.1001/jama.1960.03020120049010.
  20. ↑ Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S (1981). "Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer". N. Engl. J. Med. 304 (1): 16–21. doi:10.1056/NEJM198101013040104. PMID 7001242.
  21. ↑ Kuchera LK (1971). "Postcoital contraception with diethylstilbestrol". JAMA 218 (4): 562–3. doi:10.1001/jama.218.4.562. PMID 5171004.
  22. ↑ FDA (1975). "Diethylstilbestrol as posticoital oral contraceptive; patient labeling". Fed Regist 40 (25): 5451–5.; 40 FR 5451
  23. ↑ FDA (1975). "Estrogens for oral or parenteral use. Drugs for human use; drug efficacy study; amended notice". Fed Regist 40 (39): 8242.; 39 FR 8242
  24. ↑ Hatcher RA, Stewart GK, Stewart F, Guest F, Josephs N, Dale J (1982). Contraceptive Technology 1982–1983. New York: Irvington Publishers. pp. 152–7. ISBN 0-8290-0705-9.
  25. ↑ FDA (1978). "Estrogens for postpartum breast engorgement". Fed Regist 43 (206): 49564–7.; 43 FR 49564
  26. ↑ "Problems in Research: Regulations—The Diethylstilbestrol Tragedy". The Medical Bag. 12 April 2013. Retrieved 29 April 2014.
  27. ↑ Hammes B, Laitman CJ (Jan–Feb 2003). "Diethylstilbestrol (DES) update: recommendations for the identification and management of DES-exposed individuals.". Journal of midwifery & women's health 48 (1): 19–29. doi:10.1016/s1526-9523(02)00370-7. PMID 12589302. Retrieved 29 April 2014.
  28. ↑ Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Herbst AL, Noller KL, Hyer M, Hoover RN (Aug 2006). "Prenatal diethylstilbestrol exposure and risk of breast cancer." (PDF). Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 15 (8): 1509–14. doi:10.1158/1055-9965.EPI-06-0109. PMID 16896041. Retrieved 19 March 2014.
  29. ↑ 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. doi:10.1056/NEJM197104222841604. PMID 5549830.
  30. ↑ Troisi R, Hatch EE, Titus-Ernstoff L, Hyer M, Palmer JR, Robboy SJ, Strohsnitter WC, Kaufman R, Herbst AL, Hoover RN (2007). "Cancer risk in women prenatally exposed to diethylstilbestrol". Int. J. Cancer 121 (2): 356–60. doi:10.1002/ijc.22631. PMID 17390375.
  31. ↑ Hoover RN, Hyer M, Pfeiffer RM, Adam E, Bond B, Cheville AL, Colton T, Hartge P, Hatch EE, Herbst AL, Karlan BY, Kaufman R, Noller KL, Palmer JR, Robboy SJ, Saal RC, Strohsnitter W, Titus-Ernstoff L, Troisi R (2011). "Adverse health outcomes in women exposed in utero to diethylstilbestrol". N. Engl. J. Med. 365 (14): 1304–14. doi:10.1056/NEJMoa1013961. PMID 21991952.
  32. ↑ Office of Research on Women’s Health, NIH, DHHS (March 2006). "Status of Research on Uterine Fibroids (leiomyomata uteri) at the National Institutes of Health" (PDF). United States National Institutes of Health.
  33. ↑ Ehrhardt AA, Meyer-Bahlburg HF, Rosen LR, Feldman JF, Veridiano NP, Zimmerman I, McEwen BS (1985). "Sexual orientation after prenatal exposure to exogenous estrogen". Arch Sex Behav 14 (1): 57–77. doi:10.1007/BF0154135 (inactive 2015-01-01). PMID 3977584.
  34. ↑ Newbold RR (1993). "Gender-related behavior in women exposed prenatally to diethylstilbestrol". Environ. Health Perspect. 101 (3): 208–13. doi:10.1289/ehp.93101208. PMC 1519765. PMID 8404755.
  35. 1 2 3 Titus-Ernstoff L, Perez K, Hatch EE, Troisi R, Palmer JR, Hartge P, Hyer M, Kaufman R, Adam E, Strohsnitter W, Noller K, Pickett KE, Hoover R (2003). "Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol". Epidemiology 14 (2): 155–160. doi:10.1097/01.EDE.0000039059.38824.B2. PMID 12606880.
  36. ↑ Strohsnitter WC, Noller KL, Troisi R, Robboy SJ, Hatch EE, Titus-Ernstoff L, Kaufman RH, Palmer JR, Anderson D, Hoover RN (2010). "Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol". J. Rheumatol. 37 (10): 2167–73. doi:10.3899/jrheum.091092. PMC 2988471. PMID 20634240.
  37. ↑ Newbold RR, Padilla-Banks E, Snyder RJ, Jefferson WN (July 2007). "Perinatal exposure to environmental estrogens and the development of obesity". Mol Nutr Food Res 51 (7): 912–7. doi:10.1002/mnfr.200600259. PMID 17604389.
  38. ↑ Newbold RR, Padilla-Banks E, Snyder RJ, Phillips TM, Jefferson WN (2007). "Developmental exposure to endocrine disruptors and the obesity epidemic". Reprod. Toxicol. 23 (3): 290–6. doi:10.1016/j.reprotox.2006.12.010. PMC 1931509. PMID 17321108.
  39. ↑ Henderson BE, Benton B, Cosgrove M, Baptista J, Aldrich J, Townsend D, Hart W, Mack TM (1976). "Urogenital tract abnormalities in sons of women treated with diethylstilbestrol". Pediatrics 58 (4): 505–7. PMID 972792.
  40. ↑ Gill WB, Schumacher GF, Bibbo M, Straus FH, Schoenberg HW (1979). "Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities". J. Urol. 122 (1): 36–9. PMID 37351.
  41. ↑ Palmer JR, Herbst AL, Noller KL, Boggs DA, Troisi R, Titus-Ernstoff L, Hatch EE, Wise LA, Strohsnitter WC, Hoover RN (2009). "Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study". Environ Health 8: 37. doi:10.1186/1476-069X-8-37. PMC 2739506. PMID 19689815.
  42. ↑ Virtanen HE, Adamsson A (2012). "Cryptorchidism and endocrine disrupting chemicals". Mol. Cell. Endocrinol. 355 (2): 208–20. doi:10.1016/j.mce.2011.11.015. PMID 22127307.
  43. ↑ "Known Health Effects for DES Sons". United States Department of Health and Human Services: Centers for Disease Control and Prevention accessdate = 2011-06-30.
  44. ↑ "American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult-Male Patients--2002 Update" (PDF). American Association of Clinical Endocrinologists.
  45. ↑ Titus-Ernstoff L, Perez K, Hatch EE, Troisi R, Palmer JR, Hartge P, Hyer M, Kaufman R, Adam E, Strohsnitter W, Noller K, Pickett KE, Hoover R (2003). "Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol". Epidemiology 14 (2): 155–60. doi:10.1097/01.EDE.0000039059.38824.B2. PMID 12606880.
  46. ↑ Hood E (2005). "Are EDCs blurring issues of gender?". Environmental Health Perspectives 113 (10): A670–7. doi:10.1289/ehp.113-a670. PMC 1281309. PMID 16203228.
  47. ↑ Blackless M, Besser M, Carr S, Cohen-Kettenis PT, Connolly P, De Sutter P, Diamond M, Di Ceglie D, Higashi Y, Jones L, Kruijver FPM, Martin J, Playdon Z-J, Ralph D, Reed T, Reid R, Reiner WG, Swaab D, Terry T, Wilson P, Wylie K (2006). "Atypical Gender Development – A Review". International Journal of Transgenderism 9 (1): 29–44. doi:10.1300/J485v09n01_04.
  48. ↑ Rudacille D (2005). The Riddle of Gender (Chapter, "Fear of a Pink Planet"). Pantheon Books. pp. 240–276. ISBN 0-375-42162-9.
  49. ↑ Bao AM, Swaab DF (2011). "Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders". Frontiers in Neuroendocrinology 32 (2): 214–226. doi:10.1016/j.yfrne.2011.02.007. PMID 21334362.
  50. ↑ Reinisch JM, Ziemba-Davis M, Sanders SA (1991). "Hormonal contributions to sexually dimorphic behavioral development in humans". Psychoneuroendocrinology 16 (1–3): 213–78. doi:10.1016/0306-4530(91)90080-D. PMID 1961841.
  51. ↑ Yalom ID, Green R, Fisk N (1973). "Prenatal exposure to female hormones. Effect on psychosexual development in boys". Arch. Gen. Psychiatry 28 (4): 554–61. doi:10.1001/archpsyc.1973.01750340080013. PMID 4734959.
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